1. family and parenting
2. motherhood
3. pregnancy

REVIEW ARTICLE
Drug Safety 2001; 24 (4): 277-322
0114-5916/01/0004-0277/$22.00/0
© Adis International Limited. All rights reserved.
Risks and Benefits of Nicotine to Aid
Smoking Cessation in Pregnancy
Delia A. Dempsey1 and Neal L. Benowitz2
1 Departments of Pediatrics and Medicine, University of California, Division of Clinical
Pharmacology and Experimental Therapeutics, San Francisco General Hospital Medical Center,
San Francisco, California, USA
2 Departments Medicine, Psychiatry, and Biopharmaceutical Sciences, University of California,
Division of Clinical Pharmacology and Experimental Therapeutics, San Francisco General Hospital
Medical Center, San Francisco, California, USA
Contents
Abstract
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1. Cigarette Smoking During Pregnancy: Overview of the Problem . . . . . . . . . . . . .
2. General Pharmacology of Nicotine as Related to Reproductive Toxicity . . . . . . . .
2.1 Pharmacological Actions of Nicotine . . . . . . . . . . . . . . . . . . . . . . . . . .
2.1.1 Pharmacodynamics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.1.2 Pharmacokinetic Considerations . . . . . . . . . . . . . . . . . . . . . . . . .
2.2 Nicotine Pharmacokinetics During Pregnancy . . . . . . . . . . . . . . . . . . . . .
2.2.1 Disposition of Nicotine and Cotinine . . . . . . . . . . . . . . . . . . . . . . .
2.2.2 Plasma Concentrations Associated with Nicotine Replacement Therapy
During Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.2.3 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.3 Nicotine Disposition in the Maternal-Fetal Unit . . . . . . . . . . . . . . . . . . . . .
3. Reproductive Toxicity of Nicotine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.1 Uteroplacental Insufficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.2 Acute Effects of Nicotine During Pregnancy in Humans . . . . . . . . . . . . . . . .
3.3 Acute Effects of Nicotine in Monkeys and Sheep . . . . . . . . . . . . . . . . . . .
3.4 Rodent Studies of Long Term Nicotine Exposure and Toxicity . . . . . . . . . . . . .
3.4.1 Growth Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.4.2 Behavioural Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.4.3 CNS Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.4.4 Rodent Models of Sudden Infant Death Syndrome (SIDS) . . . . . . . . . . .
3.5 Summary and Caveat Regarding Nicotine CNS Toxicity and SIDS Data Derived
From Animals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4. Toxicity of Cigarette Smoke Upon the Pregnant Human and Fetus . . . . . . . . . . . .
4.1 Maternal Heart Rate and Blood Pressure . . . . . . . . . . . . . . . . . . . . . . . .
4.2 Fetal Heart Rate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.3 Fetal Heart Rate Reactivity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.4 Blood Flow Studies in the Fetus and Mother . . . . . . . . . . . . . . . . . . . . . . .
4.5 The Inadequacy of the Uteroplacental Insufficiency Model . . . . . . . . . . . . .
5. Toxicity of Cigarette Smoke During Pregnancy . . . . . . . . . . . . . . . . . . . . . . . .
5.1 Cellular Mechanisms of Nicotine- and Cigarette Smoking-Related Complications
of Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.1.1 Estrogen Production . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.1.2 Immunological Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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278
Dempsy & Benowitz
5.1.3 Ascorbic Acid (Vitamin C) . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.1.4 Zinc, Copper and Cadmium . . . . . . . . . . . . . . . . . . . . . . . . . .
5.1.5 Fibronectin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.1.6 Amino Acid Transport . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.1.7 Nitric Oxide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.1.8 Eicosanoids and Related Compounds . . . . . . . . . . . . . . . . . . . .
5.2 Carbon Monoxide (CO) Effects During Pregnancy and Development . . . . .
5.2.1 Interactions with Haemoglobin . . . . . . . . . . . . . . . . . . . . . . . .
5.2.2 CNS Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.2.3 Other Toxicities of CO . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6. Recommendations Regarding Nicotine Replacement Therapy During Pregnancy
– Risks versus Benefits . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.1 Efficacy Studies of Nicotine Replacement Therapy During Pregnancy . . . . .
6.2 Dose and Formulation of Nicotine Replacement Therapy . . . . . . . . . . . .
6.3 Safety Studies of Nicotine Replacement Therapy During Pregnancy . . . . . .
7. Nicotine Replacement Therapy and Breast Feeding . . . . . . . . . . . . . . . . . .
7.1 Nicotine and Cotinine Kinetics: Breast Feeding and Infant Exposure . . . . . .
7.2 The Dose of Nicotine Consumed in Breast Milk . . . . . . . . . . . . . . . . . . .
7.3 Recommendations Regarding Breast Feeding and Nicotine
Replacement Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Abstract
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Cigarette smoking during pregnancy is the single largest modifiable risk for
pregnancy-related morbidity and mortality in the US. Addiction to nicotine prevents many pregnant women who wish to quit smoking from doing so. The safety
and efficacy of nicotine replacement therapy (NRT) for smoking cessation during
pregnancy have not been well studied.
Nicotine is classified by the US Food and Drug Administration as a Pregnancy
Category D drug. Animal studies indicate that nicotine adversely affects the developing fetal CNS, and nicotine effects on the brain may be involved in the
pathophysiology of sudden infant death syndrome (SIDS). It has been assumed
that the cardiovascular effects of nicotine resulting in reduced blood flow to the
placenta (uteroplacental insufficiency) is the predominant mechanism of the reproductive toxicity of cigarette smoking during pregnancy. Short term high doses
of nicotine in pregnant animals do adversely affect the maternal and fetal cardiovascular systems. However, studies of the acute effects of NRT in pregnant humans indicate that nicotine alone has minimal effects upon the maternal and fetal
cardiovascular systems.
Cigarette smoking delivers thousands of chemicals, some of which are well
documented reproductive toxins (e.g. carbon monoxide and lead). A myriad of
cellular and molecular biological abnormalities have been documented in placentas, fetuses, and newborns of pregnant women who smoke. The cumulative abnormalities produced by the various toxins in cigarette smoke are probably
responsible for the numerous adverse reproductive outcomes associated with
smoking. It is doubtful that the reproductive toxicity of cigarette smoking is
primarily related to nicotine.
We recommend the following. Efficacy trials of NRT as adjunctive therapy
for smoking cessation during pregnancy should be conducted. The initial dose of
nicotine in NRT should be similar to the dose of nicotine that the pregnant woman
received from smoking. Intermittent-use formulations of NRT (gum, spray, in-
 Adis International Limited. All rights reserved.
Drug Safety 2001; 24 (4)
Nicotine and Smoking Cessation in Pregnancy
279
haler) are preferred because the total dose of nicotine delivered to the fetus will
be less than with continuous-use formulations (transdermal patch). A national
registry for NRT use during pregnancy should be created to prospectively collect
obstetrical outcome data from NRT efficacy trials and from individual use. The
goal of this registry would be to determine the safety of NRT use during pregnancy, especially with respect to uncommon outcomes such as placental abruption. Finally, our review of the data indicate that minimal amounts of nicotine are
excreted into breast milk and that NRT can be safely used by breast-feeding
mothers.
1. Cigarette Smoking During
Pregnancy: Overview of the Problem
It is estimated that 19 to 27% of pregnant women
in the US smoke cigarettes.[1] The adverse health
effects associated with maternal cigarette smoking
are listed in table I. There are approximately 4 million births per year in the US, and the low estimate
that 19% of pregnant women smoke cigarettes
would result in nearly 800 000 babies per year who
are exposed in utero to the products of cigarette
smoke. Cigarette smoking during pregnancy is the single largest modifiable risk for pregnancy-related
morbidity and mortality in the US. Cigarette smoke
contains thousands of chemicals, some of which
are well documented fetal toxins [e.g. carbon monoxide (CO), lead, nicotine (table II)].
Nicotine is the substance in cigarettes that is responsible for addiction to smoking. Addiction to
nicotine prevents many pregnant women who wish
to quit from doing so.[3] Nicotine replacement therapy (NRT) in nonpregnant adults increases quit
rates when used as adjunctive therapy in a smoking
cessation programme. Nicotine is classified by the
US Food and Drug Administration (FDA) as a
Pregnancy Category D drug. Category D implies
some risk during pregnancy and requires that the
risks associated with the use of the drug are outweighed by the risks of the medical problem if left
untreated. Uteroplacental insufficiency has been
the main accepted mechanism of smoking-related
reproductive adverse outcomes. According to this
mechanism, nicotine is responsible for many adverse pregnancy outcomes. It is suggested that reduced blood flow through the placenta due to the
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Table I. Cigarette smoking-related outcomes of pregnancy
Pregnancy loss
spontaneous abortion
fetal demise
stillbirths
Premature rupture of membranes
preterm
term
Premature labour and delivery
Placental abruption
Placental previa
Hypertension
Pre-eclampsia
Fetal toxicity
Growth retardation
Neurotoxicity
Cleft palates and cleft lips
Pulmonary effects
Postnatal outcomes
Sudden infant death syndrome
Premature infants, especially very low birth weight infants
Hyperviscosity in the newborn
Elevated blood pressure during infancy and childhood
Behavioural, psychiatric, and cognitive outcomes of childhood
Mental retardation
Childhood cancers
Medical conditions associated with passive smoking in
childhooda
sudden infant death syndrome
deaths due to respiratory illnesses
asthma
pneumonia and other respiratory illnesses
otitis media
burns and fire deaths
a
Increased prevalence of childhood passive smoking among
children born to mothers who smoke.
Drug Safety 2001; 24 (4)
280
Dempsy & Benowitz
Table II. Selected potentially fetotoxic chemicals in cigarettes[2]
Chemical
Dose per cigarette
Carbon monoxide
10 to 23mg
Nicotine
1 to 3mg
Hydrogen cyanide
400 to 500µg
Aniline
360 to 655µg
Catechol
200 to 400µg
Nitrogen oxide
100 to 600µg
Methanol
100 to 250µg
Phenol
80 to 160µg
Acrolein
60 to 140µg
Pyridine
16 to 40µg
Ammonia
10 to 130µg
Hydrogen sulfide
10 to 90µg
Arsenic
40 to 120µg
Hexavalent chromium
4 to 70ng
Cadmium
4 to 70ng
Nickel
0 to 600ng
Lead
34 to 85ng
Carcinogens
polynuclear aromatic hydrocarbons
60 to 190ng
heterocyclic compounds
3 to 14ng
N-Nitrosamines
200 to 4900ng
aromatic amines
30 to 670ng
N-Heterocyclic amines
40 to 300ng
aldehydes
570 to 1500ng
volatile hydrocarbons
500 to 1150ng
care may also be reluctant to prescribe a category
D drug because of legal liability fears.
Nicotine use most likely does carry some risk.
Animal data indicate that nicotine is toxic to the
developing CNS, and may be involved in the aetiology of sudden infant death syndrome (SIDS).[4]
To place the risks of nicotine in context, one must
consider the risks associated with smoking tobacco
in relation to the risks associated with NRT use.
There are at present inadequate data with which to
compare the clinical effects of cigarette smoking
and the effects of nicotine during pregnancy. Our
paper describes possible mechanisms of toxicity of
cigarette smoking during pregnancy and tries to
identify nicotine-specific toxicity versus toxicity
related to other chemicals in cigarette smoke. We
then summarise the risks and benefits of NRT use
during pregnancy, and make recommendations regarding efficacy studies and safety studies of NRT
use during pregnancy.
2. General Pharmacology of Nicotine
as Related to Reproductive Toxicity
2.1 Pharmacological Actions of Nicotine
cardiovascular effects of nicotine is responsible for
the adverse outcomes associated with smoking.
Based on the review of the literature presented
here, we conclude that it is doubtful that uteroplacental insufficiency is a major mechanism of the
toxicity of cigarette smoking or even of nicotine.
Rather, a myriad of cellular and molecular biological abnormalities produced by a number of tobacco
smoke toxins, acting alone or in concert, produce
a wide range of adverse pregnancy outcomes.
The category D status of NRT has discouraged
the investigation of NRT use during pregnancy.
Granting agencies have been hesitant to fund efficacy studies of NRT for smoking cessation during
pregnancy because of its status as a category D
drug. Drug manufacturers have not funded efficacy
studies of pharmacotherapy to aid cessation in
pregnant women. Individual providers of prenatal
 Adis International Limited. All rights reserved.
Nicotine binds to nicotinic cholinergic receptors
that are located in the brain, in autonomic ganglia,
the adrenal medulla, and in neuromuscular junctions. The receptors are believed to be receptors for
endogenously released acetylcholine. There are different subtypes of nicotinic cholinergic receptors,
composed of different subunits, different ligand
binding characteristics and different functional
characteristics. It is not clear which receptor subtypes mediate which pharmacological actions of
nicotine. Nicotine receptor activation facilitates
the release of a variety of neurotransmitters, including dopamine, noradrenaline (norepinephrine), adrenaline (epinephrine), acetylcholine, serotonin (5hydroxytryptamine), γ-aminobutyric acid (GABA),
glutamate, and β-endorphin. These effects presumably mediate the psychoactive actions of nicotine.
The main effects of nicotine on the systemic circulation is that of a weak sympathomimetic drug.
Drug Safety 2001; 24 (4)
Nicotine and Smoking Cessation in Pregnancy
2.1.1 Pharmacodynamics
The cardiovascular effects of nicotine in nonpregnant adults have been extensively studied.[3,5]
Nicotine increases heart rate and myocardial contractility, constricts some blood vessels, and transiently increases blood pressure. For additional details and references, the reader is referred to another
recent review.[3] With prolonged or repeated exposures to nicotine, many nicotine receptors become
desensitised, and tolerance develops to the effects
of nicotine via these receptors. Tolerance to the
CNS effects of nicotine is associated with an increased number of nicotinic cholinergic receptors
in the brain. Tolerance to the cardiovascular effects
of nicotine is incomplete. For example, heart rate
acceleration persists, although at less than maximal levels, despite prolonged continuous exposure
to nicotine.
The dose-response to nicotine is important in
understanding the risks of nicotine-mediated cardiovascular toxicity. Within the range of nicotine
concentrations seen in smokers, the dose-response
to heart rate acceleration and blood pressure elevation is flat, with maximal increases seen at plasma
nicotine concentrations consistent with low level
cigarette smoking. This flat dose-response curve
has been demonstrated in studies comparing smoking cigarettes with high and low nicotine-containing
tobaccos, studies of the effects of cigarette smoking with and without concomitant intravenous nicotine infusion, and studies of cigarette smoking
with and without concomitant transdermal nicotine
in doses of 21 to 63 mg/day. The flat dose-response
curve may have implications for the risks of NRT
in persons who continue to smoke cigarettes –
namely, that there is little increased risk attributable to nicotine therapy. With extremely high exposures to nicotine, such as with acute nicotine poisoning, bradycardia and hypotension associated
with nausea and vomiting occur, which is consistent with a vagotonic syndrome.
The pharmacological effects of nicotine depend
on the rate of rise of plasma concentrations in the
brain and in other target organs. Rapid administration of nicotine, such as after cigarette smoking,
 Adis International Limited. All rights reserved.
281
results in transiently high arterial nicotine concentrations and rapid delivery of nicotine to the brain.
The latter means that nicotine can have its effects
before there is time for the development of tolerance. Conversely, slow delivery of nicotine, such
as with transdermal nicotine systems, produces
less intense effects. The difference in magnitude of
nicotine effects as a function of the rate of administration is most clearly seen in psychoactive effects, which are quite pronounced with cigarette
smoking or rapid intravenous infusion, but which
are virtually nil in individuals receiving transdermal nicotine. On the other hand, while heart rate
acceleration is greater with rapid administration,
there is still heart rate acceleration even with transdermal nicotine.
One pharmacological response which may have
implications for cardiovascular toxicity is the nicotine effect on platelets and coagulation. In vitro
studies do not consistently show that nicotine activates platelets. However, some in vivo studies indicate that after rapid intravenous administration
of nicotine there is platelet activation. In studies in
dogs where platelet activation was documented,
the effect was blocked by α-adrenergic blockers,
suggesting that the effect is mediated by nicotinerelated catecholamine release. One human study
has compared cigarette smoking and transdermal
nicotine and showed no effect of transdermal nicotine upon platelet activation, whereas cigarette
smoking activated platelets. Whether a rapidly delivered nicotine bolus without other components of
cigarette smoke activates platelets remains to be
determined.
2.1.2 Pharmacokinetic Considerations
Nicotine is absorbed rapidly from cigarette
smoke, resulting in peak arterial nicotine concentrations of 50 to 100 µg/L immediately after the last
inhalation of cigarette smoke. Venous nicotine
concentrations are several-fold lower, because
nicotine in the arterial circulation has been taken
up by body tissues before it reaches the venous
circulation. The faster the rate of administration,
the larger the arterial-venous difference in blood
nicotine concentration. Thus, rapid delivery systems
Drug Safety 2001; 24 (4)
282
such as nicotine nasal spray produce greater arterial-venous nicotine differences than slower delivery systems such as transdermal nicotine. The issue
of the rate of drug delivery is important to keep in
mind in interpreting venous plasma concentration
data that are reported in various experimental studies of nicotine pharmacology and toxicology.
Once nicotine is absorbed, it moves to virtually
all body organs with particularly high affinity for
brain, the heart, and the lungs. The major storage organ for nicotine in the body is skeletal muscle, primarily because of its large mass. Nicotine concentrations in adipose tissue are low because nicotine
is a relatively polar compound. Nicotine is metabolised primarily to cotinine, but also by glucuronidation and by N-oxidation. There is nicotine
metabolism in the fetus, but it proceeds at a much
lower rate than in the mother (unpublished observation). Cotinine is important primarily because it
has been used as a marker of nicotine exposure.
Cotinine has a much longer elimination half-life
than nicotine (16 vs 2 hours in nonpregnant adults),
and concentrations in the blood are much higher for
cotinine than nicotine. Thus, cotinine is more stable and easier to measure than nicotine.
2.2 Nicotine Pharmacokinetics
During Pregnancy
2.2.1 Disposition of Nicotine and Cotinine
To the best of our knowledge, no systematic
studies of the disposition of nicotine during pregnancy have been published. We have unpublished
data on 10 women in whom the pharmacokinetics
of nicotine and cotinine were studied during pregnancy and then again 3 months postpartum.[6,7]
Several women were studied twice during pregnancy. The gestational ages varied from 17 to 40
weeks and gestational age was not found to affect
any of the pharmacokinetic parameters studied.
Nicotine
The metabolic clearance of nicotine increased
during pregnancy by a factor of 1.6.[7] During pregnancy, the mean clearance of nicotine was 1.56
L/h/kg, while 3 months after pregnancy it was 0.96
L/h/kg. This change in clearance resulted in a mod Adis International Limited. All rights reserved.
Dempsy & Benowitz
est decrease in the elimination half-life of nicotine
during pregnancy. The mean elimination half-life
of nicotine during pregnancy was 1.6 hours, while
after pregnancy it increased to 1.8 hours. The fractional conversion or the percentage of the dose of
nicotine metabolised to cotinine was unchanged by
pregnancy (76 vs 78%).
Cotinine
Pregnancy had a greater effect upon the pharmacokinetics of cotinine.[7] The nonrenal or metabolic
clearance was increased by a factor of 3. During
pregnancy, the nonrenal clearance of cotinine averaged 0.09 L/h/kg, while 3 months postpartum it
averaged 0.03 L/h/kg. This change in clearance resulted in a substantial decrease in the elimination
half-life of cotinine during pregnancy. The mean
elimination half-life of cotinine during pregnancy
was 9 hours, while postpartum the mean was 17
hours. Plasma cotinine concentrations appear to be
significantly lower during pregnancy, which alters
the correlation between cotinine concentrations
and the number of cigarettes smoked per day.[8,9]
The increased clearance of cotinine accounts at
least in part for the decreased saliva and plasma cotinine concentrations reported during pregnancy.[8,9]
2.2.2 Plasma Concentrations Associated with
Nicotine Replacement Therapy During Pregnancy
Plasma nicotine and cotinine concentrations
have been determined in a few investigations of the
short term effects of nicotine gum and transdermal
nicotine patches in pregnant women. Two studies
have reported nicotine concentrations associated
with use of transdermal patches, and 4 studies have
reported concentrations associated with chewing
gum. All the data reported here are means.
Plasma Nicotine Concentrations Associated with
Use of Transdermal Patches
Oncken et al.[10] obtained plasma nicotine samples from 15 pregnant smokers while they wore a
21mg transdermal patch for 8 hours. Blood samples were collected before and 2, 3, 4, 6, and 8
hours after patch placement. During a separate
study visit, women were allowed to smoke ad libitum, and samples were collected hourly. Based on
graphical data, plasma nicotine concentrations had
Drug Safety 2001; 24 (4)
Nicotine and Smoking Cessation in Pregnancy
reached a mean steady state level of approximately
14 µg/L by the time of the first sample collection.
There was a slight decline in nicotine concentrations over the final 4 hours of wearing the patch,
and the mean concentration was approximately 10
µg/L when the patch was removed. Plasma nicotine concentrations while on the patch were very
similar to nicotine concentrations associated with
ad libitum smoking. There is a report of nicotine
concentrations in saliva associated with patch use
during pregnancy,[11] but the results are hard to interpret. In nonpregnant adults, nicotine concentrations in saliva are 8 times greater than those in
plasma.[12] Yet in this report, the salivary nicotine
concentrations were similar to plasma concentrations reported by Oncken et al.[10] Also, there was
huge variability and fluctuations in the salivary
nicotine concentrations. For these reasons, these
data will not be reviewed here.
Ogburn et al.[8] studied 21 pregnant smokers
who wore a 22mg transdermal nicotine patch for
24 hours per day for 4 days while abstaining from
smoking on a hospital research ward. There was no
significant difference in the afternoon nicotine
concentrations seen in the women when they wore
the patch as compared to when they were smoking
ad libitum. On the first 2 days of wearing the patch,
the morning nicotine concentrations were higher
than those achieved while smoking, but on the
third and fourth hospital days there was no difference in concentrations associated with the patch or
with smoking. The plasma data indicate that nicotine patches will produce plasma concentrations in
pregnant women that are similar to those seen in
nonpregnant adults.
Plasma Nicotine Concentrations Associated
with Gum Use
Gennser et al.[13] determined nicotine plasma
concentrations in 6 pregnant smokers who chewed
2 or 4mg pieces of gum for 30 minutes. Blood samples were obtained before, and 30 and 60 minutes
after the onset of chewing nicotine gum. Thirty
minutes after chewing the 2mg gum, the mean
plasma nicotine concentration rose by 3 µg/L and
at 60 minutes it was 2.5 µg/L above the mean basal
 Adis International Limited. All rights reserved.
283
level. Chewing the 4mg gum resulted in a more pronounced rise in nicotine concentrations. After 30
minutes, the mean nicotine concentration had risen
by 9.2 µg/L and after 60 minutes the mean concentration was 6.4 µg/L above basal levels. The amount
of nicotine in the gum, before and after chewing,
was also determined. The mean amount of nicotine
released from the 2mg gum was 1.35mg, while the
mean amount released from the 4mg gum was
2.88mg. Although the 4mg gum appeared to deliver twice the dose of the 2mg gum, the change in
plasma nicotine concentrations for the 4mg gum
was 3 times that of the 2mg gum. The reason for this
is unknown.
Manning and Feyerabend[14] determined plasma
nicotine concentrations in 7 pregnant smokers after
chewing one 4mg piece of nicotine gum and in 5
women after concurrently chewing 2 pieces of 4mg
nicotine gum. The gum was chewed for 20 minutes
and the amount of nicotine released from the gum
was not determined. Blood samples were obtained
before and 30 and 60 minutes after the onset of
chewing nicotine gum. 30 minutes after chewing
the 4mg piece of nicotine gum, the mean plasma
nicotine concentration rose by 4.4 µg/L and after
60 minutes it was 3.6 µg/L above the basal concentration. For the 8mg gum, the 30 minute mean nicotine plasma concentration rose by 14.9 µg/L and
after 60 minutes the mean was 9 µg/L above the
basal concentration. A doubling of the nicotine
gum dose from 4mg to 8mg resulted in a 3.4-fold
rise in the nicotine concentration.
Lindblad et al.[15] determined plasma nicotine
concentrations in 12 pregnant smokers before and
25 and 45 minutes after chewing 1 or 2 pieces of
4mg nicotine gum. The 2 pieces of gum were chewed
1 after another, not concurrently. Each piece of
gum was chewed for 25 minutes. Based on graphed
data, 25 minutes after chewing one 4mg piece of
gum, the nicotine plasma concentration had risen
by 5 µg/L and was 3 µg/L above the basal concentration after 45 minutes. 25 minutes after chewing
2 pieces of gum, the concentration was approximately 6.5 µg/L above the basal concentration and
Drug Safety 2001; 24 (4)
284
after 45 minutes it was approximately 12 µg/L
above the basal concentration.
Oncken et al.[16] obtained blood samples from
19 pregnant smokers who chewed nicotine gum
(2mg) ad libitum (maximum 30 pieces per day) for
5 days while refraining from smoking. Women
were considered to be abstinent if exhaled CO concentrations were below 8 ppm. On average, the
women chewed between 6 and 9 pieces of gum per
day. Two of the 19 women could not maintain abstinence. Blood samples were collected on the afternoon of the fifth day. Mean peak and trough nicotine concentrations were 5.7 µg/L and 3.3 µg/ L,
respectively.
These data indicate that the gum can effectively
raise plasma nicotine concentrations during pregnancy, but the data are variable in the magnitude of
the rise in nicotine concentrations. Also, with dose
escalation, the mean plasma nicotine concentration
appeared to increase by a factor that was greater
than the increase in the dose.
2.2.3 Summary
Pregnancy affects the disposition of nicotine by
increasing the metabolic clearance of both nicotine
and cotinine. But, broadly speaking, the plasma
nicotine concentrations associated with standard
doses of NRT during pregnancy appear to be in the
therapeutic range. For any level of intake of nicotine, cotinine concentrations are significantly lower
during pregnancy, which alters the correlation between cotinine concentrations and the number of
cigarettes smoked per day.[8,9]
2.3 Nicotine Disposition in the
Maternal-Fetal Unit
The disposition of a drug between mother and
fetus are an important consideration in understanding the potential fetal toxicity of a drug taken
during pregnancy. The important anatomical elements in considering maternal-fetal drug transfer
are as follows. On the maternal side (maternal compartment), blood flows through the uterine artery
to the uterus and then through the subsidiary vessels into the placenta. The syncytiotrophoblast or
syncytium is the very thin layer of tissue in the
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Dempsy & Benowitz
placenta that separates the maternal blood from the
fetal blood. Nutrients, drugs, and waste products
cross the syncytium between the mother and fetus.
On the fetal side, the 2 umbilical arteries carry fetal
blood into the placenta and the single umbilical
vein carries blood away from the placenta back to
the fetus. The fetus is immersed in amniotic fluid.
The amniochorionic membrane, which makes and
surrounds the amniotic fluid, is adhered to the inside of the uterus not covered by the placenta.
Typically, a drug diffuses from the maternal
blood across the syncytium into the fetal blood.
Maternal drug metabolites, depending upon their
charge and concentration, may also diffuse across
the syncytium. In general, the diffusion of a drug
is dependent upon the blood concentration in the
mother and in the fetus. When the concentration is
higher in the mother, the diffusion is in the direction of the fetus. When the fetal concentration of
the drug is higher, then the diffusion direction is
towards the mother. How much drug actually diffuses from the mother into the fetus is dependent
upon the lipid solubility of the drug, the molecular
weight of the drug, and other factors. Some endogenous substances also diffuse across the amniochorionic membrane into and out of the amniotic
fluid. Transfer across the amniochorionic membrane
is also a potential route of transfer for drugs.
Nicotine moves readily from the maternal circulation into the fetus. The major route of fetal elimination is via transfer back into the maternal circulation. Data on maternal-fetal disposition of
nicotine are available from studies in sheep, (unpublished observation) monkeys[17] and directly
from humans.[18,19] Animal studies show rapid
transfer of nicotine across the placenta, with the
peak concentrations in the fetal circulation seen
within 15 to 30 minutes of maternal administration.[17] In monkeys, nicotine concentrations in
mother and fetus are similar but those in the fetus
are higher and persist for a longer period of time
than in the mother.[17] In sheep, nicotine concentrations in mother and fetus are similar. In the sheep
fetus, the clearance of nicotine is similar to umbilical blood flow, indicating that transfer of drug to
Drug Safety 2001; 24 (4)
Nicotine and Smoking Cessation in Pregnancy
the mother is the major route of elimination. Fetal
renal clearance and metabolism account for less
than 2% of total clearance in the fetal sheep (unpublished observation).
The data in humans derive from sampling maternal blood, umbilical venous blood (fetal origin)
and amniotic fluid at various times during gestation. Luck and Nau.[18,19] showed a high correlation between maternal blood and amniotic fluid
concentrations of nicotine and cotinine sampled at
16 to 24 weeks gestation. The average ratio of amniotic fluid to maternal blood concentrations was
1.54 for nicotine (n = 23) and 0.72 for cotinine (n
= 29). The ratio of mean umbilical blood to maternal blood nicotine and cotinine concentrations
were 1.12 and 1.05 in the study by Luck and
Nau[18,19] A study by Donnenfeld et al.[20] of maternal and percutaneous umbilical blood samples
obtained from pregnant women at 21 to 36 weeks
gestation found a fetal to maternal ratio for cotinine
of 0.9 (n = 11). In isolated perfused human placental cotyledons, the maternal to fetal concentration
ratio of the perfusates reached 1.0 after about 60 to
80 minutes.[21]
3. Reproductive Toxicity of Nicotine
3.1 Uteroplacental Insufficiency
Uteroplacental insufficiency has been commonly cited as the mechanism responsible for fetal
growth retardation and placental abruption associated with cigarette smoking. This hypothesis proposes that nicotine causes vasoconstriction of
uteroplacental blood vessels which reduces blood
flow to the placenta and decreases delivery of oxygen and nutrients to the fetus. The daily episodes
of transient reductions in blood flow and delivery
of oxygen and nutrients to the fetus have been postulated to be the pathophysiological mechanism of
fetal growth retardation. This hypothesis gained
widespread acceptance without solid data to support it.[22] However, the role of uteroplacental insufficiency as the mechanism of fetal growth retardation has been questioned recently because
studies of surrogate measures of blood flow in hu Adis International Limited. All rights reserved.
285
mans have failed to demonstrate an association
with fetal growth retardation except when the
changes are profound (see section 4.5).[22-25]
3.2 Acute Effects of Nicotine During
Pregnancy in Humans
The results of 42 human studies investigating
the acute cardiovascular effects of nicotine and cigarette smoking during pregnancy are presented in
appendix I. Studies which investigated nicotine are
discussed here and those which investigated cigarette smoking are presented in section 5.1. A study
in 21 pregnant smokers who wore a 22mg transdermal nicotine patch (24 hours/day) for 4 days
and received extensive monitoring over 4 days,
found no change in the maternal blood pressure or
any fetal cardiovascular effects except for a small
decrease in the fetal heart rate in the morning.[8]
This decrease was statistically but not clinically
significant.[8] No change in fetal heart rate reactivity was found.[8] There are 2 other studies in which
a nicotine patch was worn for 6 to 8 hours.[10,11]
Both studies found a gradual increase in maternal
heart rate. One study found no change in any fetal
parameters,[11] while the other found an increase in
loss of fetal heart rate reactivity compared with
cigarette smoking.[10] It is difficult to interpret the
fetal heart rate reactivity data in this study, since
the mean gestational age of the pregnancies was 28
weeks, and fetal heart rate reactivity is not a reliable measure for fetal well-being until 32 weeks
gestation.
A number of investigations have studied the effects of nicotine gum during pregnancy.[13-16,34,42]
These studies have found dose-related effects of
nicotine gum on maternal heart rate and blood
pressure, and attenuated effects on fetal heart rate
and fetal breathing. These effects are less pronounced than the effects of cigarette smoking.
Overall, nicotine patches or gum do have some
measurable cardiovascular effects during pregnancy, but the effects are small and do not appear
to compromise the mother or fetus. These effects
should not limit the use of NRT during pregnancy
in healthy smokers who wish to quit.
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286
3.3 Acute Effects of Nicotine in Monkeys
and Sheep
The acute effects of nicotine in pregnant monkeys and sheep are summarised in appendix II (includes doses, routes of administration and outcome). Prolonged enforced smoking in monkeys
resulted in a persistent drop in the maternal and
fetal arterial oxygen tension (PaO2) independent of
the presence of nicotine in the smoke.[57] Large bolus doses of nicotine in pregnant monkeys resulted
in significant cardiovascular effects, while infusions at lower doses had much smaller cardiovascular effects.[58] Nicotine infusions in the monkey
used doses that are 100 times the doses used in
humans (see appendix II).[7,58] These high doses in
monkeys resulted in a 39% decrease in uterine
blood flow, and acidosis and hypoxia in the fetus.[59]
In pregnant sheep, large bolus doses of nicotine
had significant cardiovascular effects on the ewe,
and lesser effects on the fetus.[61-64,66] At lower bolus doses of nicotine or infusions given over 10 or
more minutes, the effects were attenuated or did
not occur (see appendix II).[62,63,65,66] Although
some of these studies appear to support the uteroplacental insufficiency model, overall they do not,
because very high doses were required to demonstrate these effects, the animals were stressed
from instrumentation and the animals were often
sedated.[23] Additionally, often no effects were
found at the lowest doses used in animal studies
(see appendix II), which were still far above the
doses of nicotine delivered by smoking.
3.4 Rodent Studies of Long Term Nicotine
Exposure and Toxicity
Many rodent studies have demonstrated deleterious reproductive effects of nicotine that are separate from the cardiovascular effects of the drug.
Animal research also allows separation of the toxicity of nicotine from the toxicity of the other components of cigarette smoke. The results of studies
which examined the effects of tobacco smoke and
nicotine on pregnant animals are presented in appendix III (includes species, doses, routes of ad Adis International Limited. All rights reserved.
Dempsy & Benowitz
ministration and outcomes). The outcomes include
effects upon growth, behaviour, the CNS, the peripheral nervous system, neuroendocrine system,
blood flow, and others. The majority of the studies
used bolus or continuous parenteral nicotine administration. In most early studies, nicotine was
delivered as multiple bolus doses per day by the
subcutaneous or intraperitoneal route. These large
doses affect the cardiovascular systems of the
mother and fetus and cause ischaemic hypoxic/
anoxic damage to the fetal CNS. Later, implantable
osmotic minipumps were developed to give a continuous subcutaneous infusion that delivered a
dose more comparable to smoking or administration of transdermal nicotine.[194] This mode of administration eliminated the acute cardiovascular
effects of nicotine and enabled researchers to study
the effects of nicotine on the developing fetus in
the absence of excessive haemodynamic stress.
Few studies have reported plasma nicotine concentrations. Most investigators have relied upon
the work of Murrin et al.[194] to estimate the plasma
nicotine concentrations from the dose delivered by
osmotic pump. These authors implanted minipumps which provided continuous nicotine infusions of 0, 1.5, 4.5 or 13.5 mg/kg/day to pregnant
rats. Based on the Murrin data, for every 1
mg/kg/day of nicotine infused, the steady state
plasma nicotine level will rise by approximately 13
to 15 µg/L. A maternal nicotine dose of 6 mg/kg/
day, expected to give a plasma nicotine concentration of 80 to 90 µg/L, has consistently produced
abnormalities in the offspring of pregnant rats.
A cigarette typically delivers 1mg of nicotine to
the smoker. A woman who smokes 20 cigarettes per
day and weighs 60kg would receive a daily nicotine
dose of 0.33 mg/kg/day and would have a peak
venous plasma nicotine concentration between 15
and 30 µg/L after smoking a cigarette. This concentration falls during the time interval between cigarettes. Prior to the first cigarette in the morning,
the plasma nicotine concentration is usually at or
below 5 µg/L. In a study in which plasma nicotine
concentrations were determined in pregnant smokers after smoking and while wearing a 22mg transDrug Safety 2001; 24 (4)
Nicotine and Smoking Cessation in Pregnancy
dermal patch applied for 24 hours per day, mean
early morning venous plasma nicotine concentrations were 3.7 µg/L when smoking and 5 µg/L when
using the patch; mean afternoon plasma nicotine
concentrations were 20 µg/L when smoking and
11.2 µg/L when using the patch.[8]
Plasma concentrations associated with a continuous nicotine infusion of 6 mg/kg/day in rats are
3 to 4 times higher than the peak concentrations
seen in humans and the doses required to achieve
these concentrations are substantially higher in rats
than in humans. Although plasma concentrations
achieved in the rats are higher than those in humans, it is reasonable to extrapolate these results
to humans.
3.4.1 Growth Effects
Inhalation of cigarette smoke for even several
hours a day is the most toxic route of exposure, as
evidenced by decreased birthweight, decreased litter size, and decreased survival of offspring.[75-77,171]
Birthweight was adversely affected by tobacco
smoke even though maternal weight was unaffected. This is in contrast to nicotine administration which results in reduced maternal weights at
doses that do not reduce fetal weight.[72,137,177] Bolus doses of nicotine by gavage or subcutaneous or
intraperitoneal administration usually resulted in
birthweight reduction, decreased litter size, and decreased survival.[4] The minipump supplies a continuous dose of nicotine at daily doses that are similar to daily bolus administration and in many
studies the daily dose was the same as that delivered by bolus doses in other studies. Administration with the minipump avoids the vasoconstrictive
effects of bolus dosing.[4] The vasoconstrictive effects of nicotine are thought to be responsible for
growth retardation and decreased litter size associated with bolus administration. Interestingly, 1
study that compared the effect of nicotine and epinephrine upon uterine blood flow in late pregnancy
found that both drugs decreased uterine blood flow
and reduced maternal weight gain, but neither affected fetal weight.[72] These data suggest that
growth retardation may not be secondary to the
cardiovascular properties of bolus dosing of nicot Adis International Limited. All rights reserved.
287
ine. Minipump administration allows for the study
of the cellular toxicity of nicotine separate from the
vasoconstrictive effects of the drug. In general,
continuous delivery of nicotine by minipump usually does not affect birthweight at lower doses and
has only a minimal effect at 6 mg/kg/day.[4] The
smoking and nicotine data indicate that nicotine is
toxic to developing rodents at relatively high
doses, but that the fetal growth retardation effects
of smoking are probably due to other components
of cigarette smoke.
3.4.2 Behavioural Effects
Prenatal and perinatal nicotine exposure by any
route has been associated with dose-dependent alterations in selected behaviours and responses to
cognition tests in young and adult rodents. There
appear to be sex differences, with males more affected than females.[85,87,93,98,101,102,106] Nicotineexposed animals have exhibited alterations in spontaneous locomotion or motor activity.[84,89,98,103,105]
Other alterations were found in the righting reflex,
male sexual behaviour, some maze tests, and swimming behaviours.[86,87,99,104]
3.4.3 CNS Effects
The CNS is the primary target organ for the
toxic effects of cigarette smoking and nicotine
upon development. The development of the CNS
is very complex. There is a programme of sequential development for neurogenesis and synaptogenesis.[4] Neurogenesis begins with the proliferation of cells, then there is termination of replication
and a switch to cellular differentiation. Further development involves migration of neurons and the
development of complex cytoarchitectural configurations of various neurons. Finally, there is programmed cell death (apoptosis) of some neurons.
Synaptogenesis refers to the events required for the
development of synaptic competence. This involves the development of various types of receptors, receptor densities, synthesis of neurotransmitters, regulation of neurotransmitter synthesis,
mechanisms for transmitter release, mechanisms
for modulation and termination of receptor stimulation, and postreceptor signalling events. The setDrug Safety 2001; 24 (4)
288
point of neural activity and synaptic competence
appears to be determined during gestation.
During development, neurotransmitters have
unique trophic effects. They communicate with
genes, and neurotransmitter stimulation at specific
developmental points may initiate or terminate cellular proliferation, differentiation, migration, or
apoptosis, and may determine the set-point for neuronal reactivity which may persist into adulthood.[4] Nicotine simulates the function of a neurotransmitter at nicotinic cholinergic receptors
(acetylcholine is the endogenous ligand at these
receptors). The existence of CNS nicotinic receptors is well documented. Maternal smoking exposes the embryo/fetus to nicotine which may
stimulate nicotinic cholinergic receptors at inappropriate times during development (that is, when
acetylcholine is not normally present in significant
levels), and thus affect the development of the cholinergic nervous system. The cholinergic system
interacts with other neural projections. The adrenergic and cholinergic systems are highly interactive; therefore, during development, stimulation of
cholinergic neurons may be expected to affect the
developing adrenergic system, and possibly other
systems as well.[4]
Nicotine is thought to exerts its toxicity by interacting with nicotine receptors at inappropriate
times during gestation. There may be multiple critical times throughout human gestation when nicotine may exert a toxic effect upon nervous system
development. Rodent studies (appendix III) have
unequivocally demonstrated that exposure to
nicotine during gestation adversely affects neurogenesis and synaptogenesis in the developing
CNS.[4] Nicotine exposure during regional nicotinic receptor development in the rat results in the
most severe local adverse effects. The most severe
damage occurs in areas with the highest nicotinic
cholinergic receptor density. Initially, the midbrain
and brainstem are affected, then the forebrain (cerebral cortex), and then the cerebellum.[117] Inappropriate cholinergic stimulation appears to prematurely end cell replication and initiate cellular
differentiation in the fetal CNS, resulting in a re Adis International Limited. All rights reserved.
Dempsy & Benowitz
duced number of CNS neurons in selected areas of
the brain.[118] These events occur at nicotine doses
that do not cause growth retardation, and often full
recovery does not occur after nicotine is stopped.
Gestational nicotine exposure appears to have
wide ranging effects upon synaptic competence
(appendix III).[4] Various studies have demonstrated effects of nicotine upon transmitter synthesis,
release, and turnover in the fetal or neonatal brain.
The affected transmitters include acetylcholine,
noradrenaline, dopamine, and serotonin.[134,145,146] A
variety of alterations in the receptors for these neurotransmitters after exposure to nicotine have also been
found and include alterations in receptor type, receptor density, receptor binding capacity, and G proteinmediated receptor density.[115,120,124,130,136,138,141]
3.4.4 Rodent Models of Sudden Infant Death
Syndrome (SIDS)
The mechanisms responsible for SIDS are unknown and are probably multifactorial. Maternal
smoking during gestation increases the risk of
SIDS[195] and, independent of prenatal exposure,
postnatal passive smoking by the infant also increases the risk of SIDS.[195,196] Epidemiologically,
it is difficult to separate prenatal and postnatal exposure. One hypothesis predicates that SIDS results from an abnormality in the cardiovascular and
respiratory response to hypoxia (assumed to be secondary to transient sleep apnoea or transient airway
obstruction).[159] In the normal rat, the adrenal medulla of the fetus and neonate is not innervated. In
response to hypoxia, there is massive catecholamine release by the adrenal medulla, which redistributes blood flow to the brain and heart and maintains the heart rate during an episode of hypoxia.
The neonatal rat is dependent upon a response to
hypoxia by the adrenal medulla that is independent
of central reflexes. Eventually the adrenal medulla
is innervated and loses its autonomous response to
hypoxia.
Some neonatal rats that have had long term exposure to nicotine in utero lose their autonomous
adrenal response to hypoxia before innervation and
the development of central reflexes.[151,159] Nicotine appears to prematurely switch off the autonoDrug Safety 2001; 24 (4)
Nicotine and Smoking Cessation in Pregnancy
mous response to hypoxia. This provides a window
of vulnerability to hypoxia. A proportion of these
animals, in response to hypoxia, do not release catecholamines. During hypoxic stress, they develop
bradycardia and die. The rat studies were somewhat extreme in comparison to the human situation. The gestational dose of nicotine was 6
mg/kg/day and the hypoxic insult was 60 or 75
minutes of 5% oxygen.[4] These data may still be
relevant to humans for the following reasons. Fetal
and young rats are much more tolerant to hypoxia
than humans. SIDS has a low incidence and animal
studies can only model infrequent human events by
employing high doses of potentially causative
agents and extreme measures. Whether adrenal catecholamine release in response to hypoxia is a
valid model for the human pathophysiology of
SIDS remains to be determined.
3.5 Summary and Caveat Regarding
Nicotine CNS Toxicity and SIDS Data
Derived From Animals
Clearly, nicotine is a neuroteratogen. The animal data demonstrate that nicotine is toxic to the
developing CNS. The question is how to apply
these animal data to humans; specifically, how
should these data affect recommendations for NRT
during pregnancy? In an individual woman, should
the dose of nicotine in NRT be limited to no greater
than that which she receives from smoking? Although nicotine is a CNS fetal toxin, cigarette
smoke also delivers other CNS fetal toxins. CO is
a well documented fetal neurotoxin (section
5.2).[197] We know little about the fetal toxicity
from the thousands of other compounds in tobacco
smoke. The potential human toxicity of nicotine
must be balanced against the combined toxicity of
nicotine, CO, and the other compounds in cigarette
smoke. Animal studies that compare the nervous
system toxicity of nicotine with that of tobacco
smoke are generally lacking. The growth data indicate that inhaling cigarette smoke for a few hours
a day is more toxic than relatively large doses of
nicotine. It is doubtful that the smoking regimens
in the animal studies delivered a nicotine dose
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289
comparable to those delivered by bolus injection
or continuous minipump infusion, yet 1 rat study,
involving 4 hours per day of tobacco smoke exposure, found reduction in cell number in the hindbrain.[112] It cannot be assumed from these animal
studies that the fetal toxicity found in epidemiological studies of pregnant smokers is attributable to
nicotine because there are so many fetal toxins in
cigarette smoke and the nicotine doses used in
these animal studies were high relative to the doses
delivered by cigarettes or NRT.
4. Toxicity of Cigarette Smoke Upon the
Pregnant Human and Fetus
Studies of the acute effects of smoking 1 to 2
cigarettes after overnight abstinence are the predominant data used to support uteroplacental insufficiency as the mechanism responsible for many
adverse reproductive outcomes such as fetal
growth retardation and placental abruption. It is
important to review these studies because they are
the basis for concerns regarding the acute toxicity
of nicotine upon reproduction (even though there
are actually studies of smoking cigarettes).
40 studies in humans have investigated the
acute effects of cigarette smoking or nicotine upon
the maternal cardiovascular system or upon the fetus (appendix I).
4.1 Maternal Heart Rate and Blood Pressure
In 1 study of 292 nonsmokers and 203 smokers,
no differences in basal maternal heart rates were
found.[27] An acute elevation in maternal heart rate
and in systolic and diastolic blood pressure was
commonly found with smoking a cigarette (appendix I). The increases were dose-dependent. Heart
rate elevations were not associated with placebo
gum or with smoking 1 herbal (non-nicotine) cigarette, but were associated with smoking 2 herbal
cigarettes.[15] The effects of smoking upon maternal heart rate and blood pressure were modest and
transient.
Drug Safety 2001; 24 (4)
290
4.2 Fetal Heart Rate
25 studies have investigated the effects on cigarette smoking or nicotine upon the fetal heart rate.
Newnham et al.[27] performed serial fetal sonograms at 18, 24, 28, and 34 weeks of gestation in
263 nonsmokers, 29 quitters, and 203 smokers.
They found no significant association between fetal heart rates and maternal smoking, but did find
the usual dose-dependent decrease in birthweight.
A small study[28] of 19 nonsmokers and 5 smokers,
which also involved serial fetal sonograms, did
find that after 35 weeks gestation there was a statistically significant but not clinically significant
elevation in the fetal heart rate in smokers compared to nonsmokers (144 vs 132 beats/min).
Among the remaining 23 studies, smoking 1 to 2
cigarettes generally resulted in a transient elevation
in the fetal heart rate, while chewing nicotine gum,
wearing a nicotine patch, or smoking herbal cigarettes did not result in an elevation in the fetal heart
rate. One study comparing ad libitum smoking with
ad libitum nicotine gum did find an elevation in the
fetal heart rate after chewing gum; but the effect of
the gum upon the fetal heart rate was less than that
of smoking (appendix I).
4.3 Fetal Heart Rate Reactivity
Various measures of fetal activity have been
evaluated for their ability to predict fetal well-being.
The modified Biophysical Profile (BPP) is the
most widely used and accepted measure to assess
the well-being of the fetus.[198] The validity of its
use for surveillance for fetal well-being has been
confirmed.[198,199]
The modified BPP consists of a fetal nonstress
test (NST) and an amniotic fluid index (AFI). The
NST consists of an unprovoked, continuous measurement of the fetal heart rate using ultrasound. A
reactive NST is an immediate indicator of fetal
well-being. After 32 weeks of pregnancy, the vast
majority (90 to 99%) of NSTs in normal fetuses
should be reactive.[200,201] In clinical practice, the
majority of NSTs are performed after 32 weeks.
The NST is less useful before 32 weeks gestation,
because of the high rate of false positives.[200,201]
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Dempsy & Benowitz
The AFI is a measure of the amniotic fluid volume
by ultrasound and reflects the long term adequacy
of placental function. A reactive NST and an AFI
between 5 and 25cm constitutes a normal (or negative) modified BPP. A BPP is usually done weekly
in high risk pregnancies.
10 studies have investigated fetal heart rate reactivity. There are different ways that fetal heart
rate reactivity is reported in the literature. More
recently, NST results have been reported as reactive or nonreactive. Earlier studies reported increased or deceased short term reactivity (also
known as the differential index, DI) and long term
reactivity (also known as the interval index, II). A
decrease in short and long term reactivity is similar
to a nonreactive NST. Phelan[26] followed 478 high
risk pregnancies, of whom 128 mothers were
smokers. The smokers and nonsmokers had similar
high risk diagnoses, except that intrauterine growth
retardation (IUGR) was more common and preeclampsia significantly less common among smokers. 13% of the nonsmokers and 21% of the smokers had nonreactive NSTs (p < 0.005). Among the
nonsmokers with nonreactive NSTs, the NSTs remained nonreactive at subsequent NSTs which is
associated with a poor prognosis; among the smokers, the subsequent NSTs were often reactive indicating a transient effect of smoking upon the NST,
consistent with frequent false positive NSTs among
smokers. A transient decrease in fetal heart rate reactivity has been consistently found in studies
where the fetal heart rate reactivity was monitored
before and after smoking 1 or 2 cigarettes (appendix I).
4.4 Blood Flow Studies in the Fetus
and Mother
Four arteries, 2 uterine and 2 ovarian, supply the
maternal placental circulation. These arteries extensively arborise before they reach the placenta.
By the time they reach the placenta, they have become funnel shaped, low resistance, dilated uteroplacental arteries which lack a muscular layer.
Across this branching arterial system there is a
large drop in blood pressure. The anatomic changes
Drug Safety 2001; 24 (4)
Nicotine and Smoking Cessation in Pregnancy
that occur and the great drop in pressure across the
arterial system of the pregnant uterus allow for increased blood flow to the placenta as pregnancy
advances. Blood flow in this complex system cannot be studied directly in humans because it requires radioactive isotopes. Blood velocity or the
systolic : diastolic ratio are surrogate measures of
flow blood and can be determined by Doppler studies. Doppler studies of these surrogate measures in
the placenta and fetus are not sensitive predictors
of outcome except when the changes are profound.[24,25]
19 studies examine various parameters of fetal
blood flow, such as cardiac output, blood vessel
diameter, velocity indices, etc. In general, there are
transient effects in response to cigarette smoking,
chewing nicotine gum, or wearing a nicotine patch.
A large prospective study of basal umbilical artery
systolic : diastolic ratios found no significant difference among 535 nonsmokers, quitters, light
smokers, and heavy smokers.[27] A much smaller
study of 19 nonsmokers and 5 smokers found that
among smokers there was a significant increase in
basal aortic blood flow, and in mean and peak aortic blood flow velocities.[28]
It is difficult to summarise the fetal blood flow
data because they are inconsistent, and often different parameters are reported (pulsatile indices,
resistance indices, velocity, velocity indices, systolic : diastolic ratios, blood flow) which are not
easily compared. Studies, even by the same authors, have reported data suggestive of no change
in fetal aortic blood flow,[29,33,34,55] increased fetal
aortic blood flow,[15,29,30,202] and decreased fetal
aortic blood flow.[15] Similarly, contradictory results have been reported for umbilical artery, umbilical vein, and uterine artery blood flow parameters. Even the few studies of intervillous blood
flow in the placenta have been contradictory.
Lehtovirta and Forss[39] reported that overall there
was a decrease in the mean intervillous blood flow
after smoking a cigarette which returned to baseline within 15 minutes. But an examination of the
data revealed that 5 of 12 women in the study had
increased intervillous blood flow.[39] Other stud Adis International Limited. All rights reserved.
291
ies[40,41,46] have also reported inconsistent findings
within the same type of study. Studies of smoking
or nicotine gum or patches in healthy pregnancies
mainly confirm that nicotine has modest, transient
pharmacological effects upon the cardiovascular
system in the mother and fetus.
4.5 The Inadequacy of the Uteroplacental
Insufficiency Model
There are a number of problems with uteroplacental insufficiency as an explanation for the deleterious effects of smoking upon the fetal-maternal
unit. These studies were conducted in the morning
after overnight abstinence and required that the
mother vigorously smoke the cigarette. The acute
response to smoking is maximal with the first cigarette, and some studies involved smoking 2 cigarettes in succession. With repeated administration,
tolerance develops to the effects of nicotine. In
nonpregnant adults the effects occurring in the
morning are greater than the effects occurring
through the day. Many human studies, as summarised in appendix I, found statistically significant differences in uteroplacental blood flow before and after smoking 1 to 2 cigarettes. But the
clinical significance is not obvious since the
changes are often within normal limits.
Fetal growth retardation associated with cigarette smoking begins in the first trimester. During
the first 2 trimesters, the fetus is so small that the
placenta can easily deliver more than adequate nutrition to the fetus, and uteroplacental insufficiency
cannot be a mechanism for fetal growth retardation. Possibly, during the third trimester, uteroplacental insufficiency may contribute to fetal growth
retardation because of rapid fetal growth. In general, Doppler studies during pregnancy have been
unable to correlate placental blood flow or systolic
: diastolic ratios with pregnancy outcome, except
among severely growth-retarded fetuses where
there is reverse diastolic blood flow.[24,25] The
physiology of maternal blood flow in the placenta
is that of a low pressure system designed to maintain fetal oxygenation and nutrition during labour
when very strong contractions lasting 60 seconds
Drug Safety 2001; 24 (4)
292
are reducing blood flow to the placenta. The maternal and fetal blood vessels on either side of the
placenta lack musculature and are unresponsive to
vasoactive agents. Physiologically, it is difficult to
envision a system that can accommodate labour,
but cannot accommodate the minor increases in
vascular resistance associated with smoking.
Animal studies have found that nicotine does
reduce blood flow to the fetal placental unit (see
appendix II and section 3.3). But Lambers and
Clark,[23] who conducted some of these animal
studies and have written an extensive review, found
them inadequate as an explanation for the deleterious effects of smoking upon pregnancy. Animal
studies usually involve very high doses of nicotine.
The animals are instrumented, which is stressful to
the mother and fetus. Sedation, which is required
to maintain instrumentation, may alter the haemodynamics of nicotine and could accentuate their
cardiovascular effects.
The vascular effects of nicotine were the first
effects to be demonstrated, but may not be the most
important mechanism of the deleterious effects of
smoking. The myriad of cellular effects presented
in the next section and in appendix IV indicate that
the pathophysiology of smoking-induced adverse
reproductive effects are complex and many occur
at the cellular level. The haemodynamic effect of
nicotine is one of the many effects of cigarette
smoking and uteroplacental vasoconstriction alone
is insufficient to explain placental abruption or fetal growth retardation. The lack of data to support
the uteroplacental insufficiency model is important
when considering the use of NRT during pregnancy. The greatest concern about adverse effects
of NRT on the mother during pregnancy has been
that nicotine will acutely affect placental blood
flow. However, the data reviewed above (section
4.4) suggest that NRT does not significantly decrease placental blood flow.
5. Toxicity of Cigarette Smoke
During Pregnancy
Cigarette smoking exposes the fetus to more than
3000 chemicals in smoke.[2] The major toxic com Adis International Limited. All rights reserved.
Dempsy & Benowitz
ponents in cigarette smoke are nicotine, CO, ammonia, nitrogen oxide, hydrogen cyanide, hydrogen
sulfide, acrolein, methanol, pyridine, phenol, aniline,
many carcinogens, lead, and other metals (table
II).[2] Different toxins in cigarettes might cause
similar adverse outcome. Nicotine, CO, and lead are
all fetal neurotoxins.
5.1 Cellular Mechanisms of Nicotineand Cigarette Smoking-Related
Complications of Pregnancy
In the past 2 decades, many cellular effects of
cigarette smoking upon the uterus, placenta, and
fetus have been discovered and these actions may
be more important than the vascular effects of
nicotine. In this section (and in appendix IV) we
review these cellular effects and discuss selected
mechanisms of toxicity. It is important to note that,
in general, the mechanisms involved in the adverse
outcome of pregnancy are incompletely understood. The mechanisms underlying premature rupture of membranes, fetal growth retardation, placental abruption, placenta previa, etc., are believed
to involve multifaceted pathogenic pathways, but
their actual pathophysiology is still obscure.[269]
For a particular adverse outcome, changes (hormone levels, enzyme expression or activity, cellular morphology, etc.) have been observed, but how
the various changes are integrated into a whole and
which are the most important is often unknown.
The changes associated with maternal smoking
must be viewed in the context of limited understanding of the underlying pathophysiological processes. Usually the smoking data are too limited to
ascertain if the observed effect of smoking has a
clinically significant involvement in an outcome.
5.1.1 Estrogen Production
Plasma levels of estrogen in pregnant smokers
are approximately 90% of those found in nonsmokers.[232,241] During pregnancy, most estrogen
is formed by the placenta from androstenedione
supplied by the fetal adrenal glands. The reaction
is catalysed by placental aromatase. Heavy smokers have lower placental aromatase activity than
nonsmokers.[242] Nicotine, cotinine, and anabasine
Drug Safety 2001; 24 (4)
Nicotine and Smoking Cessation in Pregnancy
(a constituent of cigarette smoke) all inhibit the
conversion of androstenedione to estrogen.[240]
Subsequently, it was found that 2 other constituents of cigarette smoke and tobacco leaf, N-Noctanoylnornicotine and N-(4-hydroxyundecanoyl)
anabasine,[243,244,270] are competitive inhibitors of
aromatase and are significantly more potent inhibitors than nicotine. The effect of smoking upon estrogen production illustrates an important general
point – multiple chemicals in cigarette smoke may
share the same toxic effect.
5.1.2 Immunological Effects
Smoking is associated, in a dose-dependent
manner, with premature rupture of membranes, especially when it occurs prior to 33 weeks.[271-273]
The mechanisms whereby smoking contributes to
preterm rupture of membranes and preterm labour
are not known. Numerous lines of evidence indicate that focal damage to the membranes results in
their subsequent rupture;[269] and that focal infection and inflammation appear to be common causes
of focal damage.[269] Smoking could increase the
risk of infection-induced preterm rupture of membranes by lowering local immunity and facilitating
the ascent of vaginal micro-organisms into the
uterine cavity.[274-276] Smoking has been shown to
affect the immune system in the nonpregnant tissues, and may have similar effects in the reproductive tract. Macrophages of smokers have decreased
phagocytic capability.[277] In mucosal tissue, such
as the vagina, immunoglobulin (Ig)A is an important nonspecific defence mechanism. Salivary IgA
is decreased in nonpregnant adult smokers.[275]
The secretory component of IgA is 50% higher in
the serum of pregnant smokers.[257]
5.1.3 Ascorbic (Vitamin C)
Premature rupture of membranes, especially
prior to 32 weeks gestation, is associated with
smoking. The tensile strength of the amniochorionic membrane is predominately attributable to the
collagen layer of the amnion.[269,278] Ascorbic acid
(vitamin C), primarily obtained from amniotic
fluid, is required for the biosynthesis of collagen
by amnion epithelial cells.[279] Low ascorbic acid
levels are associated with premature rupture of
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293
membranes.[280] Reduced availability of ascorbic
acid may impair the strength of the amnion and
facilitate rupture of membranes. The ascorbic acid
concentration in amniotic fluid is reduced by 50%
among smokers.[281] Reduced ascorbic acid levels
in smokers are independent of dietary intake,[282]
but are a result of the increased utilisation of ascorbic acid as an antioxidant to detoxify the oxidant
gases of cigarette smoke. Additionally, placental
villous calcifications are increased among smokers, and this abnormality is lessened by increasing
the maternal intake of ascorbic acid, betacarotene
and tocopherol (vitamin E).[215] Other smokingrelated effects upon collagen can be found in appendix IV. Finally, a relative ascorbic acid deficiency may impair immune function.[281,283] Thus,
smoking, via its effect upon ascorbic acid, could
facilitate infection during pregnancy.[284,285]
5.1.4 Zinc, Copper and Cadmium
Zinc- and copper-containing enzymes are found
in all tissues, including pregnancy-related tissues.
Zinc is important for the stabilisation of membranes. Zinc metalloproteinases are found in the
amnion and placenta and are important in maintaining the intracellular matrix that contributes to
the strength of the amnion. DNA and RNA polymerases are also zinc-containing enzymes. Amniotic fluid zinc is involved in antibacterial activities.
A copper enzyme, lysyl oxidase, is required for
cross-linking of collagen and elastin which are
necessary to produce the tensile strength of the amnion. Deficiencies in both copper and zinc may
have a role in the pathogenesis of preterm rupture
of membranes. Both lower maternal blood zinc and
lower maternal and cord blood copper levels have
been found among women with preterm rupture of
membranes, and among women with term pregnancies whose membranes have ruptured prior to
labour.
Cadmium from cigarette smoking may affect
levels of both zinc and copper during pregnancy.
Cigarette smoking is the major source of cadmium
even among those living near cadmium-emitting
industries.[286-290] Cadmium has an elimination
half-life of 7 to 30 years, so that cadmium accumuDrug Safety 2001; 24 (4)
294
lates in the bodies of smokers. Maternal smoking
affects umbilical cord blood and placental zinc
concentrations.[286,291-293] This may be attributable
to the trapping of zinc in the placenta by cadmium[286,294] Smoking during pregnancy appears
to adversely affect older women disproportionately, and this might be attributable to the accumulation of cadmium associated with years of smoking.[292] There may also be an interaction between
cadmium and copper in the placenta[294] and in amniotic fluid.[295] In cell culture, cadmium inhibits
procollagen production,[296] and its effect upon amnion metallothionein may limit the availability of
copper to lysyl oxidase, the enzyme that cross-links
collagen.[295]
5.1.5 Fibronectin
Fibronectin is a glycoprotein formed by many
tissues including the placenta and amnion.[297] It is
found in high concentrations in maternal blood and
amniotic fluid. It is thought to be important in intracellular adhesion, including the adhesion of the
placenta to the decidua basalis.[298] Among pregnant smokers, amnionic fibronectin output is decreased while placental fibronectin output is increased.[219] In cultured fibroblasts, fibronectin
production is inhibited by cigarette smoke extract.[299] The extract was less inhibitory after removal of the volatile components. Acrolein and acetaldehyde, 2 volatile components, individually
inhibited fibronectin production.[219]
5.1.6 Amino Acid Transport
Amino acid transport across the placenta is disrupted by maternal smoking.[300,224] Nicotine or
cotinine may not be the responsible agents, since
they do not inhibit transport of a probe amino acid
in placental vesicles or perfused placental tissues.[223] In placental vesicles, nicotine was found
to inhibit glycine transport on the fetal side but not
on the maternal-facing basal membrane.[225] Theoretically, disruption of the transport of essential
amino acids may interfere with protein synthesis
and contribute to impairment in the strength of the
amnionchorionic membrane.[269]
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Dempsy & Benowitz
5.1.7 Nitric Oxide
Nitric oxide is a potent myometrial relaxant,[297]
but whether or not it has a significant role in preterm labour is unclear.[301] Nitroglycerin, a nitric
oxide donor drug,[297,301] is an effective tocolytic.[297] Maternal smoking is associated with decreased placental nitric oxide synthetase activity[222] and decreased production of nitric oxide
precursors in umbilical arteries.[221] In vascular endothelial cells, smoking impairs release of nitric
oxide and this is reversed by antioxidants, indicating that oxidant stress is responsible for the inhibition.[302] Smoking could contribute to preterm labour by its effect upon nitric oxide.
5.1.8 Eicosanoids and Related Compounds
Platelet activating factor (PAF) and prostaglandins are believed to be involved in the initiation and
maintenance of labour at term. Platelet activating
factor is secreted by the term fetus into the amniotic
fluid. As PAF levels rise, phospholipase A is activated which releases arachidonic acid that results
in prostaglandin synthesis. Amniotic fluid levels of
prostaglandins rise during labour. Infection is commonly associated with preterm labour. Bacterial
contamination of the amniotic fluid will induce release of cytokines from monocytes. Cytokines are
known to activate phospholipase A, which releases
arachidonic acid which is in turn metabolised to
prostaglandin E2 and prostaglandin F2α. Cytokines also stimulate PAF synthesis which stimulates prostaglandin synthesis. As prostaglandin
levels rise in amniotic fluid, uterine contractions
start. This cascade of events occurs prior to the development of clinical chorioamnionitis. Cigarette
smoking may contribute to preterm labour by its
effect upon PAF. PAF is inactivated by PAFacetylhydrolase. Components of cigarette smoke
(other than nicotine and cotinine) inactivate PAFacetylhydrolase.[256] Reduced inactivation of PAF
due to smoking would allow more PAF to cross the
amniochorionic membrane or placenta and reach
the myometrium.[301] Other effects of cigarette
smoking upon eicosanoids may be found in appendix I.
Drug Safety 2001; 24 (4)
Nicotine and Smoking Cessation in Pregnancy
5.2 Carbon Monoxide (CO) Effects During
Pregnancy and Development
CO merits its own section because it is present
in substantial concentrations in tobacco smoke and
is a well established reproductive toxin. The dose
of CO per cigarette is 10 to 20 times the dose of
nicotine. CO is a potent fetal toxin. Accidental
symptomatic maternal exposures to CO from
which the mother makes a full recovery may result
in stillbirth or permanent neurological damage to
the fetus.[197,303,304] There is a large body of literature regarding the fetal effects of CO.[197]
5.2.1 Interactions with Haemoglobin
CO tightly binds to maternal and fetal haemoglobin at sites that normally bind oxygen with an
affinity that is over 200 times that of oxygen.[305]
Carboxyhaemoglobin (COHb), the carbon monoxidehaemoglobin complex, has an elimination half-life
of 5 to 6 hours. The COHb concentration in the
blood of smokers averages 5 to 10%. At steady
state, there is a linear correlation between maternal
and fetal carboxyhaemoglobin (r = 0.8).[306-308] Fetal haemoglobin binds CO more avidly than adult
haemoglobin, and fetal levels of COHb are higher
than maternal levels.[307] There is a lag of up to 7
hours before there is full equilibration between fetal and maternal COHb levels.[307] In vivo data on
fetal and maternal carboxyhaemoglobin give a fetal/maternal ratio of 1.8,[308] although this varies
with the time interval between smoking and sample collection.[306] The long elimination half-life of
CO in the maternal blood and the lag between maternal-fetal equilibrium means that CO does not
clear from the fetus during maternal sleep.
The elevated COHb in smokers results in a functional anaemia and stimulates erythrocyte production. Thus, elevated haematocrits are seen in pregnant smokers and in their fetuses.[226,259,261] The
elevated haematocrit increases the viscosity of the
blood and places the newborn at risk for stroke and
exchange transfusions.[258,309] This effect upon
haematocrit and viscosity may adversely affect the
placenta.[261] Data indicate that higher maternal
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295
blood viscosity is a risk factor for suboptimal placental perfusion.[310]
CO impairs oxygen release from haemoglobin
to tissue.[307,311] When oxygen rich blood flows
through tissue capillary beds, the low tissue oxygen tension precipitates the release of oxygen from
haemoglobin. The fetus functions on the steep part
of the oxyhaemoglobin dissociation curve and a
small decrease in oxygen tension results in a major
decrease in haemoglobin saturation and unloading
of oxygen.[312] CO shifts the oxyhaemoglobin dissociation curve to the left, which means that the
oxygen tension of the blood decreases to lower
than normal values before a given amount of oxygen will be released from haemoglobin. This impairs transfer of oxygen from the mother to the fetus,
and from fetal blood to fetal tissue. Thus, CO results
in chronic cellular hypoxia in the fetus.[307,311,313]
Cellular hypoxia may be a mechanism for fetal
growth retardation associated with maternal cigarette smoking. In animals, even mild long term CO
exposure with maternal COHb levels in the 4 to 9%
range resulted in fetal growth retardation.[314,315]
The carboxyhaemoglobin levels associated with
smoking are between 5 and 10%.
5.2.2 CNS Effects
The deleterious effects of CO exposure upon the
developing CNS are well documented in animals
and in humans.[197,303] CNS abnormalities were
found among fetuses and pups of pregnant rats
chronically exposed to CO concentrations that produced maternal COHb levels (11.5 to 27%) at or
slightly above those seen in smokers.[316-322] Similar abnormal findings to the above have been reported after nicotine exposure in the rat (see appendix III). Behavioural studies of animals prenatally
exposed to CO have revealed persistent postnatal
effects associated with exposure that produced maternal COHb levels in the 6 to 16% range.[319,323-329]
5.2.3 Other Toxicities of CO
In animals, CO exposure is associated with fetal
cardiac hypertrophy.[197,330-332] An elevated resting
heart rate has been noted among adult rats who
were exposed to CO in the early postnatal period.[176] Alterations in levels of various growth
Drug Safety 2001; 24 (4)
296
factors have been found among pups after long
term exposure to CO.[197] There are 2 other possible
general mechanisms whereby CO could affect the
developing CNS. First, CO binds to other heme-containing proteins besides haemoglobin.[334] Hemecontaining proteins are ubiquitous in the body. Secondly, CO may function as a neurotransmitter, in a
manner similar to nitric oxide,[335-337] and might
result in inappropriate receptor simulation during
fetal development. CO is undoubtedly detrimental
to fetal growth and development.
6. Recommendations Regarding
Nicotine Replacement Therapy During
Pregnancy – Risks versus Benefits
Human and animal data indicate that the risk of
cigarette smoking during pregnancy is far greater
than the risk of exposure to pure nicotine. However, the use of NRT is not without potential risks,
and the magnitude of the risk of NRT to the mother
and fetus is unknown. On balance, the use of NRT
to aid smoking cessation during pregnancy seems
reasonable. However, at this time, our primary
recommendation is that NRT be studied in clinical
trials as adjunctive therapy for smoking cessation
during pregnancy for women who are unable to
quit with behavioural therapy alone. Two research
questions need to be addressed in clinical trials.
First, is NRT efficacious; does it increase smoking
cessation? Second, is it safe; what is the true risk
of use to the mother and child? NRT could turn out
not to be efficacious during pregnancy because the
women who would require NRT are the most heavily addicted and the least able to quit even with the
assistance of NRT. From an ethical perspective, efficacy and safety should be studied concurrently.
No pregnant woman should take NRT unless there
is personal benefit. The fetal risk associated with
nicotine exposure, as indicated by animal studies,
mandates that the safety of long term exposure be
studied. Pharmacokinetic studies should be conducted within the context of efficacy studies.
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Dempsy & Benowitz
6.1 Efficacy Studies of Nicotine
Replacement Therapy During Pregnancy
The efficacy of NRT for smoking cessation should
be studied during pregnancy. NRT should be studied within the context of a behavioural smoking
programme, which will enhance overall cessation
rates. Efficacy studies should collect safety data as
an integral component of their design, even if underpowered to detect some adverse outcomes. Efficacy studies should not be delayed awaiting
safety study results. Efficacy studies should not be
delayed awaiting the completion of pharmacokinetic studies or animal studies.
6.2 Dose and Formulation of Nicotine
Replacement Therapy
The goal of NRT is smoking cessation, working
primarily through reduction of withdrawal symptoms including craving. An obvious safety goal is
to limit the exposure of the mother and fetus to the
minimum effective dose of nicotine. The NRT formulation used in efficacy studies should deliver the
lowest total dose of nicotine to achieve control of
withdrawal symptoms and craving. Although safety
considerations will be used to make recommendations regarding selection of a particular formulation and dose of nicotine, ultimately the selection
of a formulation and dose must rest on its ability to
achieve smoking abstinence in an individual
woman.
We suggest that intermittent-use formulations
are preferred because they deliver a lower total
daily dose of nicotine than formulations that provide continuous drug delivery. Intermittent-use
formulations include nicotine gum, nicotine spray,
and the nicotine inhaler. The transdermal patch, a
continuous-use formulation, is less preferred because it delivers a greater total dose of nicotine than
intermittent-use formulations. If used, the patch
should initially be worn for only 16 hours a day,
unless it is unable to provide control of withdrawal
symptoms. Use for 16 hours is reasonable because
available clinical data indicate that use of transdermal patches for 16 or 24 hours per day is equally
effective.[338] The initial dose of nicotine in NRT
Drug Safety 2001; 24 (4)
Nicotine and Smoking Cessation in Pregnancy
should be matched to the usual dose of nicotine that
the mother receives from smoking.
Each study should develop a decision algorithm
for continuation or termination of NRT in the event
of continued smoking. It is recommended that
cotinine, exhaled CO, and/or carboxyhaemoglobin
levels be measured frequently to assess compliance with treatment. The duration of nicotine use
during pregnancy should be limited to those typically used in smoking cessation programmes (6 to
12 weeks), and the dose should be weaned over
time.
6.3 Safety Studies of Nicotine Replacement
Therapy During Pregnancy
All efficacy studies should be designed to collect safety data. The statistical power of an efficacy
trial and a safety study are very different. Very large
safety studies will be required to measure infrequent or rare events like premature delivery or placenta previa. To overcome this limitation, a registry for NRT pregnancy efficacy trials should be set
up to pool safety data. A pregnancy registry for
NRT should be set up that collects prospective data
from efficacy trials and from individual obstetrical
care providers who prescribe NRT during pregnancy. Obstetrical standards of practice require
that all prenatal care providers and hospital obstetrical services collect specific data on all pregnancies so collection of pregnancy outcome measures
would not be an onerous task to include in efficacy
studies.
7. Nicotine Replacement Therapy
and Breast Feeding
The impact of nicotine and other pharmacotherapies on the infant postpartum is of concern because of the importance of achieving and/or maintaining smoking cessation in mothers of infants.
The major issue with maternal drug use postpartum
is the potential exposure of their infants to drugs
via ingestion of breast milk, and adverse consequences thereof.
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297
7.1 Nicotine and Cotinine Kinetics:
Breast Feeding and Infant Exposure
The dose of a drug taken in by an infant during
breast feeding is the product of the concentration
of the drug in breast milk and the volume of milk
consumed by the baby. In neonates, the volume of
milk ingested is about 900ml per day, increasing to
1500ml per day as the baby grows. The concentration of a drug in breast milk may vary according to
when the drug is taken by the mother relative to
when the baby is breastfed. When the mother
smokes a cigarette, there is an important difference
in the route of nicotine exposure between the
mother and the baby. The mother’s exposure is via
the lungs, while the baby absorbs the nicotine
through the gastrointestinal tract. There is considerable first pass metabolism of nicotine after oral
administration (metabolism by the liver before entry into the systemic circulation). In adults, the systemic bioavailability of nicotine after oral administration is 25 to 50%.[339] The oral bioavailability
of nicotine in the infant is not known, but is likely
to be much less than 100%.
Nicotine is both water soluble and lipid soluble,
and distributes rapidly to and from breast milk. As
maternal plasma concentrations rise, breast milk
concentrations rise also and as maternal plasma
concentrations fall, the concentration of nicotine in
the milk within the breast falls. The systemic dose
of nicotine to the mother is 1 to 2mg per cigarette,
or 21mg per day per 21mg patch worn for 24 hours,
or 15mg per day for a patch worn for 16 hours.
Nicotine has a large volume of distribution and
only a small fraction of the absorbed dose remains
in the plasma. The nicotine in breast milk is acquired
from the mother’s plasma. There is a high degree
of correlation between concentrations of nicotine in maternal serum and in breast milk ranging
from r = 0.7 to r = 0.94.[18,19,340] The concentration
of nicotine is substantially higher in breast milk
than in serum, with average ratios of 2.5 to 2.9. Nicotine concentrations are higher in breast milk than in
plasma because the pH of breast milk is relatively
acidic (6.8 to 7.0) compared with serum (7.4). At
a breast milk pH of 6.9, the Henderson-Hasselbach
Drug Safety 2001; 24 (4)
298
equation predicts a milk-serum ratio of 2.45 and at
a breast milk pH of 6.8, a ratio of 3.13, consistent
with the observations noted above.
Nicotine leaves the milk within the breast at a
similar rate to its elimination from the maternal
plasma. This was determined in 5 women who refrained from smoking for 4 hours and gave repeated breast milk samples during the abstinence
interval. The mean elimination half-life of nicotine
from breast milk was 95 minutes, similar to the
elimination half-life in serum (81 minutes). Because of the rapid movement of nicotine from serum into and out of breast milk, the level of nicotine
in the milk is highly dependent on how many cigarettes have been smoked since the last breast feeding, and the time of the last cigarette prior to breast
feeding.[19]
7.2 The Dose of Nicotine Consumed
in Breast Milk
The concentration of nicotine in milk in 21
mothers after smoking a cigarette averaged 55 µg/
L,[340] while the average level of nicotine in milk
over 24 hours was 18 µg/L in 10 mothers smoking
1 to 10 cigarettes per day; 28 µg/L in 11 mothers
smoking 11 to 20 per day, and 48 µg/L in 13 mothers smoking 21 to 40 cigarettes per day.[19] Assuming a breast milk nicotine level associated with
smoking greater than 20 cigarettes per day, the dose
of nicotine given to the baby would be 45 µg/day
(50µg nicotine/L breast milk X 0.9 l/day). For a
4.5kg baby, this dose represents 10 µg/kg/day.
Using the more direct approach of measuring
nicotine concentrations in the milk of individual
mothers and estimating milk consumption by
weighing their infants before and after a feeding,
Dahlstrom et al.[340] determined an average daily
nicotine dose of 6 µg/kg/day. Since the infant is
taking nicotine orally with some degree of first
pass metabolism, the systemic dose is probably
even less than the 6 or 10 µg/kg/day estimated by
these 2 methods. In contrast, the nicotine intake in
a 70kg adult smoking 20 cigarettes per day or using
a 21mg nicotine patch is about 300 µg/kg/day.
Thus, even with maternal exposure consistent with
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Dempsy & Benowitz
a high level of NRT (i.e. 21mg transdermal patch)
the daily exposure normalised for the weight of the
infant is more than 50 times less than the exposure
of the mother. Serum concentrations of nicotine
have been measured in 8 infants of breast-feeding
mothers and were found to be quite low (range >0.2
to 1.6 µg/L) with an infant to maternal serum ratio
of 0.06 supporting the idea that infant exposure is
quite low.[19]
7.3 Recommendations Regarding
Breast Feeding and Nicotine
Replacement Therapy
Nicotine is present in breast milk and the infant
does get exposed to nicotine, but the resulting concentrations are quite low compared to that of an
adult smoker or an adult using NRT. It is unlikely
that the low level of exposure is hazardous to the
infant. In contrast, there is good evidence that exposure to environmental tobacco smoke by the respiratory route is hazardous to the infant. Thus,
provision of NRT to the mother, if that results in
her not smoking, would be of great potential benefit to the infant. On balance, the benefits of breast
feeding and smoking abstinence during the postpartum period greatly outweigh the risks of NRT in
the postpartum period.
Breast milk production is lower in smokers
compared to nonsmokers. It is unknown what components of cigarette smoke are responsible for the
reduced milk production. If something other than
nicotine is responsible, then NRT for smoking abstinence postpartum may have an additional benefit of preserving breast milk production. Theoretically, the formulation of NRT may affect the level
of nicotine in breast milk. Transdermal nicotine
would provide a steady level of nicotine in plasma
and thus in breast milk, and the mother could not
control the level of nicotine in breast milk except
by changing the strength of the patch. Mothers who
use NRT intermittently (gum, nasal spray, or inhalation) might minimise the nicotine in their milk by
prolonging the duration between nicotine administration and breastfeeding.
Drug Safety 2001; 24 (4)
Nicotine and Smoking Cessation in Pregnancy
8. Conclusion
299
Appendix I
Nicotine has been shown to be toxic to the developing fetus in animal studies. Cigarette smoke
contains thousands of chemicals, many of which
are also reproductive toxins. The foremost toxin in
cigarette smoke is carbon monoxide, a potent fetal
toxin. Nicotine replacement products are not completely without risk, but their risk is much less than
that of cigarette smoke. We recommend that the
efficacy of nicotine replacement products for
smoking cessation be studied during pregnancy.
Intermittent delivery formulations of NRT are the
preferred formulation during pregnancy because
they would be expected to give a smaller daily dose
than a continuous delivery formulation such as a
patch. Ultimately, the selection of a formulation
and dose must rest on its ability to achieve smoking
abstinence in an individual woman. We recommend the creation of a pregnancy registry for NRT
that collects prospective obstetric outcome data
from efficacy trials and from individual prenatal
providers who have prescribed the NRT during
pregnancy. As regards breastfeeding, we recommend the use of NRT for smoking cessation for
women who breastfeed. The dose of nicotine delivered in breast milk from NRT will be very small,
the risk to the baby is minimal and the benefit of a
smoke-free environment is large.
Acknowledgements
Research supported in part by the Robert Wood Johnson
Foundation and grants No. DA02277 and DA12393 from the
National Institute on Drug Abuse, National Institutes of
Health. The authors thank Kaye Welch for editorial assistance.
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Drug Safety 2001; 24 (4)
Nicotine and Smoking Cessation in Pregnancy
© Adis International Limited. All rights reserved.
Appendix I. Acute effects of cigarette smoking or nicotine on the mother and fetus
No. of patientsa
GA
Dose and
Maternal nicotine
(wk)
dosage form plasma
administered concentrationb (µg/L)
Maternal Maternal Fetal
HR
BP
HR
Fetal
blood
flow
Altered
Comment
uteroplacental
blood flow
350 nonS
32-40
128 S
32-40
292 nonS
18-34
↔
↔
↔
↔
203 S
18-34
↔
↔
↔
↔
Results of NST: 13% of nonS were NR
and remained NR on a subsequent NST;
21% of smokers were NR (p < 0.01 vs
nonS), but may not have remained NR on
subsequent NST
20-38
Control Control
20-38
↑
Yes
34-40
↑
Yes
↑
Yes
1 cig
17
1 cig
19
33-39
↑
26
Smoking was not allowed before or during 27
the protocol
Smoking was not allowed before or during 28
the protocol
29-31
Effects on fetal aorta: ↑diastolic diameter,
↑pulse amplitude,↑ slope of ascending
curve; ↓duration of ascending curve
32
Continued on next page
299
Drug Safety 2001; 24 (4)
19 nonS
5S
10
Reference
300
© Adis International Limited. All rights reserved.
Appendix I. Contd
No. of patientsa
Dose and
Maternal nicotine
GA
dosage form plasma
(wk)
administered concentrationb (µg/L)
Maternal Maternal Fetal
HR
BP
HR
Fetal
blood
flow
30
1 cig
26
33-39
↑
Yes
12
1cig
41.3
33-39
↑
↔
6
1 herbal
7.9
33-39
↔
↔
6
2mg gum
10.4
33-39
↑
↔
6
4mg gum
17.4
33-39
↑
20
4mg gum
↑
↑
Altered
Comment
uteroplacental
blood flow
Reference
33
Effects on fetal aorta: ↑diameter, ↑peak
and mean blood velocity, ↑flow; Effects on
UV: ↑diameter, ↑mean blood velocity, ↑flow
Maternal effects: ↑HR correlated with
nicotine plasma concentration; Fetal
effects: periodically ↑FB and apnoeic
episodes (cig only)
13
Maximum nicotine plasma concentration =
12 µg/L; Effects on fetal aorta: ↔blood
flow or FVW; Effects on UA and UV:
↔blood flow or FVW
34
Effects on UV: sig changes in cig groups
only
15
Fetal effects: ↓ long term HR variability
35
Fetal effects: ↓short term and long term
HR variability
36
↔
↑
↑
↔
↔
↔
1 cig
17
33-36
↑
↑
↑
Yes
2 cig
24
33-36
↑
↑
↑
Yes
12
1 herbal
2.5
33-36
↔
↔
↔
↔
12
2 herbal
2.5
33-36
↑
↔
↔
↔
12
4mg gum
7
33-38
↑
↑
↔
↔
12
8mg gum
12
33-36
↑
↑
↔
Yes
12
placebo gum 1
33-36
↔
↔
↔
↔
8
1 cig
22-26
↑
↑
↑
8
1 cig
37-41
↑
↑
8
1 cig
27-32
↑
↑
↑
Fetal effects: variable transient changes in 37
short and long term HR variability
8
1 cig
37-40
↑
↑
↔
Fetal effects: transient changes in short
and long term HR variability
38
12
1 cig
35-40
↑
↑
Effects on IBF: ↓ in 7 cases, ↑ in 5 cases;
overall ↓ at 5 min, resolved by 15 min
after smoking
39
12
1 cig
↑
↑
Yes
1 cig
↑
↑
Yes
Effects on IBF: ↓ in normotensive
patients; ↑ IBF in those with hypertension
40
11 hypertensive
Yes
Dempsey & Benowitz
Drug Safety 2001; 24 (4)
24
24
Effects on IBF: variable change (↑, ↓ and
↔)
41
Yes
↔
↔
Effects on FVW S/D: sig ↑ in UA among
those who smoked >10 cig/d
42
Yes
47
1 cig
26-39
35
2mg gum
26-39
19
2 cig
25 high risk
patients
1 cig
31-44
19
1 cig
29-39
↔
12
2 cig
39-45
↑
40
2 cig
>34
2 cig
↑
↑
23
1 cig
↑
↑
51
1 cig
34-38
10
2 cig
34-38
10
2 cig
37-40
5
cig
6
21mg patch
19
27-38
↑
↔
↔
↔
15
21mg patch
16
24-36
↑
↑
↔
15
ad lib cig
19.7
24-36
↑
↑
↔
↑
↑
Yes
↑
↔
↑
↔
Effects on UA: baseline S/D above 90% in 43
13 participants, sig ↓S/D; Effects on
resistance index: sig ↓
No participants became NR on NST; Fetal
effects: transient ↑HR
44
Effects on fetal aorta and UV: ↔blood
flow or diameter
33
↑
45
Yes
Abnormal scan in 4 patients
46
Maternal effects: NS ↑ in plasma
dopamine levels, rapid ↑ in adrenaline
plasma levels, slow ↑ in plasma cortisol
levels, ↔ in PRL, hPL or E3 levels
47
Fetal effects: ↔ in fetal cerebral arteries;
Effects on UA: ↔ in resistance indices
48
Fetal effects: ↓ short term variability; ↓FM
on monitor (but not by maternal report);
changes in FHR and FM returned to
baseline in <1h
49
Fetal effects: ↑FB, ↔ in apnoeic
episodes; ↓FM (maternal report)
50
Fetal effects: some sig changes in HR
variability
51
Effects on UA: sig ↑ in pulsatile index
52
↔
↔NST; ↔HR accelerations; Effects on
UA: ↔blood flow, ↔S/D
11
Yes
Yes
10
Maternal effects: ↑ resistance index in
uterine artery; Fetal effects: ↑ resistance
index in middle cerebral artery, loss of HR
reactivity - 1/15 (patch) vs 7/15 (cig; p =
0.058); Effects on UA: ↑ resistance index;
Yes
Yes
↑
↔
↑
↔
↑
Yes
Continued on next page
301
Drug Safety 2001; 24 (4)
1 cig
Nicotine and Smoking Cessation in Pregnancy
© Adis International Limited. All rights reserved.
Yes
7
302
© Adis International Limited. All rights reserved.
Appendix I. Contd
No. of patientsa
GA
Dose and
Maternal nicotine
(wk)
dosage form plasma
administered concentrationb (µg/L)
Maternal Maternal Fetal
HR
BP
HR
Fetal
blood
flow
Altered
Comment
uteroplacental
blood flow
Reference
9
ad lib cig
24-36
↑ cig>
gum
Yes
Yes
16
15
2mg ad lib
gum
24-36
Yes
Yes
Maternal effects: drop out rate 1/10 (cig)
vs 4/19 (gum); ↓ in uterine artery
resistance index (gum > cig); Effects on
UA: ↓ in resistance index (cig > gum)
15
1 cig
↑
±
↑
Yes
Yes
Maternal effects: ↑ S/D in uterine artery
Effects on UA: sig ↑S/D at 5, 10 and 15
min, return to baseline within 30 min
53
21
1 cig
↑
±
↑
Yes/↔
Fetal effects: sig ↑HR (from 146 to 152
bpm) for <10 min, ↔fetal cardiac output
and other fetal doppler parameters
54
7
1 cig
↑
↑
↑
↔
Fetal effects: sig ↑HR (from 136 to 142
bpm); fetal aorta: ↔blood flow velocity or
systolic or diastolic diameter
55
18
2 cig
23-38
Fetal effects: sig ↑ in duration of apnoeic
episodes
56
Fetal breathing effects: cig sig ↑; herbal
gradual ↑, 4mg gum no change, 8mg gum
sig ↑
14
19 normal
2 cig
15
28 high risk
2 cig
?
10
2 herbal
low
7
4mg gum
7.6
5
8mg gum
16.2
↑
↑
cig>
gum
↔
There was no nonsmoking control groups in any of the studies except for those by Phelan,[26] Newnham et al.[27] and Eldridge et al.[28] In all other studies, smokers served as
their own control; after overnight abstinence, the mother and/or fetus would be assessed and then a cigarette would be smoked, or gum chewed, or a transdermal patch
applied, after which the assessment was repeated.
b
After smoking a cigarette, chewing gum or wearing a transdermal patch.
bpm = beats per minute; BP = blood pressure; cig = tobacco cigarette; E3 = estrogen E3; FB = fetal breathing; FHR = fetal heart rate; FM = fetal movement; FVW = flow velocity
waveform; GA = gestational age in weeks since last menses; herbal = herbal cigarette; hPL = placental lactogen; HR = heart rate; IBF = intervillous blood flow; nonS = nonsmoker;
NR = nonreactive; NS = nonsignificant; NST = nonstress test; PRL = prolactin; S = smoker; S/D = systolic/diastolic ratio; sig = statistically significant; UA = umbilical arteries; UV =
umbilical vein; ↑ = increased; ↓ = decreased; ↔ = no change between before and after, or no difference between exposed and control groups, or not altered.
Dempsey & Benowitz
Drug Safety 2001; 24 (4)
a
Animal
Monkey
Route
IH
Dosage
Cigarette
Nicotine
Monkey
IV
6.7-11.6mg
Nicotine
Tobacco
smoke
Monkey
Sheep
IV
IH
0.1 mg/kg x 20min
Cigarette
Nicotine
Tobacco
smoke
Sheep
Sheep
IV
IH
2.5 to 5 mg/kg
8 to 9 cigarettes
Nicotine
Sheep
IV
0.14 to 0.85 mg/kg
Nicotine
Sheep
IV for
10 min
Nicotine
Sheep
IV
0.5, 1.0, 1.5mg infused over
10 minutes (or 0.014-0.032
mg/kg/min)
15mg infused over 10min
Outcome
Cigarette smoke delivered by sealed helmet over mother’s head for 30 min. Animals acted as their
own controls and there was a nicotine-free herbal cigarette group. ↔maternal and fetal HR or SBP;
both nicotine and non-nicotine cigarette resulted in persistent ↓PaO2 which was still present 30 min
after exposure to smoke
Nicotine was infused 1h after surgery in sedated monkeys. Maternal dosages were based on
weight; fetal dosages were based on estimated weight. 4 experiments:
A - Maternal bolus dose (1 mg/kg or 6.7 mg): immediate ↑maternal SBP and ↓HR with severe arrhythmias and hyperventilation, all returned to baseline in 15-20min; ↔ABG. The fetal response was
similar but ↓SBP was persistent; fetuses ≥GD 120 developed acidosis with small sig ↓PaO2 and
↓%O2 saturation; 2/9 fetuses died
B - Maternal infusion dose (100 µg/kg x 20 min or 11.6mg): maternal ABG changes were consistent
with mild hyperventilation. Fetuses ≥GD 120 developed persistent ↓PaO2 and ↓%O2 saturation
C - Fetal bolus dose (1.1-1.6 mg/kg): fatal haemodynamic changes similar to those seen with
maternal administration, but attenuated; slight ↓pH, otherwise no changes in fetal ABG. No change
seen in mothers
D - Fetal infusion dose (70 µg/kg/min x 30 min): gradual ↑fetal HR and ↓BR. ↑maternal HR and
SBP during infusion and slight ↓HR and SBP after infusion
Uterine BF ↓38%; fetus became acidotic and hypoxic
Pregnant ewes were monitored for 6h after inhalation of 1 cigarette smoked via tracheal tube.
Maternal CO-Hb ↑ at 10min (from 2.4 to 8.3%); ↓ to 2.7% after 6h. Fetal CO-Hb ↑ from 5.1 to 7.1% by
3h and was 7% at 6h
Experimental conditions unclear. Nicotine infusion and/or smoking appeared to occur 1-2h after instrumentation of ewe and fetus. 8-9 cigarettes were smoked in 1h by intubated ewes. Probable nicotine bolus dose administered to ewe or fetus: 2.5-5.0 mg/kg. After maternal nicotine infusion:
↓maternal SBP and uterine BF, then sustained ↑ in both. ↔ in fetal HR, SBP or umbilical BF. After
fetal nicotine infusion: similar changes noted, but 2-3 times the maternal dose was required. After
smoking: ↔ in maternal HR and SBP, fetal HR and SBP, maternal or fetal ABG, umbilical vein BF;
sig ↑CO-Hb, but not fetal CO-Hb
Nicotine dosages:
A = 0.14-0.25 mg/kg by rapid bolus injection in carotid artery (A1) or jugular vein (A2) of ewe.
B = 0.27-0.85 mg/kg infused over 30 min in jugular vein of ewe.
C = 0.025-1.0mg bolus into fetal carotid artery
Results:
A: brief ↓ then ↑ for 10-30min in maternal HR; ↑ maternal and fetal SBP, ↓ fetal HR, ↓ fetal PaO2, ↓
fetal breathing after 10 minutes; ↔ uterine arterial blood pressure or maternal ABG;
B: ↔ in fetal or maternal ABG, SBP, HR;
C: ↑ fetal SBP, HR and breathing; ↔ in fetal ABG
0.5mg dose: ↔ effects; 1.0 and 1.5mg dose: initial ↑ in uterine BF, then prompt ↓ to mean
maximum of 44%, ↑ mean uterine VR (from 0.07 to 0.22 mm Hg/ml or 203%), direct infusion of
nicotine into uterine artery produced no change in BF
Most parameters returned to baseline by 60 min. ↑ maternal HR (from 97 to 116 bpm), SBP (from
91 to 119mm Hg) and pH (from 7.47 to 7.5), ↑ fetal HR (from 197 to 215 bpm); ↓ uterine BF (29%),
fetal SBP (from 53 to 50mm Hg); ↔ in fetal PaO2 or %O2 saturation
Reference
57
58
59
60
61
62
63
64
Continued on next page
303
Drug Safety 2001; 24 (4)
Toxin
Tobacco
smoke
Nicotine and Smoking Cessation in Pregnancy
© Adis International Limited. All rights reserved.
Appendix II. Effects of smoking or acute nicotine infusion in pregnant sheep and monkeysa
Toxin
Nicotine
Animal
Sheep
Route
IV
Dosage
7.5, 15, 22.5mg infused over
15 minutes
Nicotine
Sheep
IV
0.2 mg/min x 5 min, dose
repeated q30min for 4 hours
(i.e. 1mg x 8)
3, 10, 20, 30 µg/kg/min for 10
min with 5-10 minute intervals
between each increase
Outcome
Peak plasma nicotine concentrations were 130, 250, and 350 µg/L respectively. 0.5 mg/min: ↔ in any
maternal or fetal haemodynamic parameters or plasma noradrenaline or adrenaline levels; 1.0 or
1.5 mg/min: sig ↓ uterine BF; sig ↑ maternal SBP; 1.5 mg/min: sig ↑ maternal and fetal
noradrenaline/adrenaline plasma levels
Mean nicotine plasma concentrations were 23 µg/L (post-infusion) and 4 µg/L (pre-infusion). ↔
maternal HR, SBP, noradrenaline or adrenaline plasma concentrations and uterine BF
Reference
65
304
© Adis International Limited. All rights reserved.
Appendix II. Contd
66
67
3µg: ↔; 10µg: minimal effect; As dose ↑ further: ↑ maternal SBP (from 79 to 121mm Hg), ↓ fetal
HR (from 174 to 153 bpm) and SBP (from 55 to 69mm Hg), ↓ uterine BF (from 1237 to 719 ml/min or
42%), ↑ uterine VR (from 0.07 to 0.2 mm Hg/min or 344%), and ↔ in maternal HR or fetal ABG (PaO2
oxygen content, PCO2, pH); 20 and 30µg: ↓FHR; 30µg: modest ↓ in umbilical BF (from 554 to 449
ml/min) and ↑ umbilical VR (from 0.11 to 0.16mm Hg/ml)
Nicotine
Sheep
IM
5mg twice daily for 5 days
Unexposed control and placebo groups were included in the study. Vascular resistance was
68
examined by transcutaneous Doppler on GD 80, 100, 130. Stillbirths: 10% of controls vs 62% of
nicotine-exposed; premature delivery: 0% in controls vs 42% of nicotine-exposed animals; no
differences in maternal or fetal HR or uterine resistance index; placental and umbilical resistance
indices tended to ↑ late in gestation; at GD 130 ↑ in fetal cerebral resistance index; after birth ↓
vascular response to carbon dioxide challenge
a The animals were anaesthetised and the mother and fetus were surgically instrumented and catheterised. Prior to study, there was usually more than 48h recovery from
surgery, unless otherwise stated. All values reported are means. In most studies, animals served as their own controls.
ABG = arterial blood gas; BF = blood flow; bpm = beats per minute; BR = breathing rate; CO-Hb = carboxy-haemoglobin; FHR = fetal heart rate; GD = gestational day; h = hour;
HR = heart rate; IH = inhalation; IM = intramuscular; IV = intravenous; PaO2 = arterial oxygen tension; PCO2 = carbon dioxide tension; SBP = systolic blood pressure; sig = statistically
significant; VR = vascular resistance; ↑ = increased; ↓ = decreased; ↔ = no significant change.
Nicotine
Sheep
IV
Appendix III. Pregnant animal toxicity studies of tobacco smoke and nicotine
Toxin
Animal
Route
Blood flow and related studies
Smk
Monkey
IH
Smk
Mice
IH
Nic
Guinea pigs pb
Nic
Rats
Outcomeb
Reference
Acute
Both tobacco and herbal cigarettes caused drop in fetal PaO2 suggestive of CO effect
Fetal blood vessel abnormalities
Nic plasma concentrations: 72 µg/L (4.5µg/min dosage) and 315 µg/L (18 µg/min dosage); at high
dosage only – decreased cardiac output and uteroplacental blood flow, rise in adrenaline but not
noradrenaline
40% reduction in uterine blood flow with 5mg dosage and reduced uterine oxygen tension
GD 13-19; severe maternal growth retardation in both groups; fetal weights unaffected; greater
than 40% reduction in uterine blood flow; vasoconstriction alone does not affect fetal growth
57
69
70
4.5 or 18 µg/min
pb
mp
0.5 or 5
2.4, 4.8, 9.6
mp
149 µg/h
1.5, 5
Poorly developed decidual basalis (placenta); increased incidence of hydrocephaly; no growth
retardation or effect upon survival
Functional disorders of the placenta
71
72
73
74
Continued on next page
Dempsey & Benowitz
Drug Safety 2001; 24 (4)
Nic
Rat
Nic or
Rat
adrenaline
Placental studies
Nic
Rat
Daily dosage
mg/kg/da
IH
IH
pb
po
Nic
Rat
po
Nic
Smkless tob
Rat
Rat
po
po-g
6
3 or 12
Smkless tob
Rat
po-g
4, 12, 18
Nic
Nic
Rat
Rat
pb
pb
6
1.5 or 3.0
Nic
EtOH
Nic
Nic
Nic
Nic
Nic
Nic
Rat
pb
6
Guinea pigs
Rats
Mice
Rat
Rat
Mice
pb
pb
pb
pb
pb
pb
6
0.5
0.9, 1.8, 2.7
0.5
1, 3, 5
Nic
Nic
Rat
Rat
mp
4
Nic
Nic
Rat
Rat
mp
mp
2
2
Nic
Rat
mp
6
Daily
Altered open field activity; decreased number of litters and survival
Similar learning of avoidance conditioning in all 3 groups; cigarette exposure – growth retardation
82
83
Increased motor activity both sexes; maternal growth retardation; fetal growth retardation in
males only
Altered behaviour in males; basal cortisol levels decreased in both sexes, no effect on stress
cortisol levels; reduced male number and birth weight but no effect on female birth weight
Both sexes – impairment in performance in radial arm maze
Maternal and fetal growth retardation; increased death in high dosage group; male pups righted
faster; poor performance – swimming development; many other behavioural tests – no difference
At the 2 higher dosages maternal and fetal growth retardation; incidence of death increased in a
dose dependant manner; normal pinna and incisor development, earlier eye opening and vaginal
patency; numerous behaviour tests – some difference found in higher dosage groups
Altered locomotor activity
Altered behaviour in neonates and adults; no maternal or fetal growth retardation but altered
organ/body weight ratios including brain
Behavioural effects with interaction between nic and EtOH; more stillbirths and neonatal death
with combined exposure
Behavioural alterations in neonates and adults
Avoidance conditioning: improved in females, reduced in males
Postnatal audiogenic seizures – prolonged latency, delayed onset and extinction
Decreased ambulatory activity
Poorer performance on both learned and innate behaviour measures as juveniles and adults
Delayed postnatal development: bodyweight gain, eye opening, body hair growth, sensory motor
reflexes. Motor – persistent hyperactivity
Altered motor activity, males only
Fetal growth retardation; after propranolol challenge – poorer cognitive function as assessed by a
maze
Testing on PND 50; subtle cognitive abnormalities, with sex differences
Increased fetal mortality, decreased weight gain postpartum, normal acquisition of developmental
milestones; nic and lobeline challenge on PND 14; in males only – greater locomotor activity s/p
nic, and greater stereotypy s/p lobeline
In females – alteration in acoustic startle response
84
85
86
87
88
89
90
91
92
93
94
95
96
97
98
99
100
101
102
Continued on next page
305
Drug Safety 2001; 24 (4)
Behavioural studies
Smk
Rat
Nic vs Smk vs Rats
control
Nic
Rat
75
76
77
78
79
80
81
Nicotine and Smoking Cessation in Pregnancy
© Adis International Limited. All rights reserved.
Growth studies (many studies in other section contain growth data)
Smk
Rat
IH
7 min 16 /d
Fetal growth retardation
Smk
Rat
IH
2h/d
Reduced fetal weight compared to pair fed group
Smk
Rat
IH
2h/d
Fetal growth retardation, complete catch up by 2 wks old; control groups: pair fed and ad libitum
Nic
Rat
pb
30
Maternal and fetal growth retardation
Nic
Rat
pb
5
Reduced embryo cell cleavage and cell number, reduced oviduct blood flow
Nic
Rat
pb
0.1, 1
No maternal or fetal growth retardation at low dosage, but retardation at 1 mg/kg/day
Nic
Rat
Patch
1.75, 3.5
Pregnancy failure 100% at 3.5mg dosage; 25 to 50% pregnancy failure at 1.75 dosage
depending on duration of use
Toxin
Animal
Nic
Nic
Nic
Rat
Rat
Rat
Nic
Rat
Route
Daily dosage
mg/kg/da
1.5
0.25
2
Combined behavioural and central nervous system studies
Nic
Mouse
pb
0.13
Nic
Nic
Rat
Mouse
pb
pb
2
3
Nic
Rat
mp
6
Nic
Rat
po
1, 4
Central nervous system studies
Smk
Rat
IH
4 h/d
Rat
po
Nic
Rat
po
Nic
Rat
po
Nic
Rat
pb
Nic
Rat
pb
3
Nic
Rat
pb
3
Nic
Rat
pb
3
6
Reference
Increased spontaneous locomotor activity
Decreased male sexual behaviour, correlated with decreased testosterone levels
Alterations in motor development, specificity of alteration dependent upon time of gestational exposure
to nic
No maternal or fetal growth retardation; subtle alterations in cognitive performances, with sex
differences; decreased responsiveness to adrenergic challenge (propranolol)
103
104
105
Postnatal nic PND 10-16: behaviour – hypoactivity; alteration in the proportion of high and low
affinity receptor binding sites
No behaviour changes in pups; increased susceptibility to electroconvulsive shock.
Poorer performance in 8-arm and Morris mazes, and in spatial probe tests; altered hippocampal
muscarinic receptors
Study of males; brains of exposed hyperactive males had increased nicotinic cortical receptor density
without a change in binding affinity, when compared to nonhyperactive males or even to hyperactive
controls
Postnatal exposure PND 4-12; reduced hippocampal electrophysiological response to auditory
stimuli
107
106
108
109
110
111
Brain regions analyzed for DNA, protein, and cholesterol content; antenatal exposure – no effect;
postnatal exposure – hindbrain reduced DNA with increased protein/DNA ratio indicating
reduction in cell number and increase in cell size
Mild increase in dead cells in medulla; normal postnatal respiratory response. Decreased birth
weight
112
Male rats only: adrenaline levels elevated in cortex and hypothalamus during infancy; adrenergic
receptor binding increased in cortex in adults
PND 14 – reduced M1 and M2 muscarinic sites and corresponding mRNA in selected brain
regions, resolved by PND 35
Desynchronisation of ontogenic patterns of DNA, RNA and proteins, persistent ODC activity, DNA
suppression, growth retardation greatest in cerebellum least in brainstem and mid-brain
Growth retardation, including brain; elevated transmitter turnover in noradrenergic pathways;
order of magnitude of effect: cerebellum > cerebral cortex > mid-brain and brain stem;
noradrenergic pathways more vulnerable than dopaminergic pathways; peripheral sympathetic
nervous system – cardiac, renal, adrenal and lungs also affected; CNS affected prior to PNS
Nic caused stimulation of ODC within 1 hr of drug administration with time and region specificity.
ODC regulates polyamine biosynthesis and thus regulates cell differentiation; 3 areas of brain
differ in time course of maturation and in nicotinic receptor concentration: midbrain + brainstem
(earliest and highest), forebrain (intermediate profiles), cerebellum (latest time and fewest
receptors)
Inhibition of DNA synthesis by rank order of nic receptors: midbrain, brainstem ≥ cerebral cortex >
cerebellum
114
113
115
116
117
118
119
Dempsey & Benowitz
Drug Safety 2001; 24 (4)
Nic
Outcomeb
306
© Adis International Limited. All rights reserved.
Appendix III. Contd
pb
3
Nic
Rat
pb
2.5
Nic
Rat
pb
0.3
Nic
Rat
pb
1
Nic
Rat
pb
0.4
Nic
Rat
mp
Nic
Rat
mp, pb
Nic
Rat
mp, pb
Nic
Rat
mp
1.5
Nic
Rat
mp
2
Nic
Rat
mp
6
Nic
Rat
mp
Nic
Rat
mp
6
Nic
Nic
Rat
Rat
mp
mp
6
2
Nic
Rat
mp
2, 6
Nic
Rat
mp
2, 6
Nic
Rat
mp
Transient alteration in somatostatin-like immunoreactivity and in receptor number, that normalised
by day 30 of life
Fetal and brain growth retardation; cellular ultrastructural changes noted, and reduced thickness
of cell layers
Ability of nic to cause catecholamine release paralleled the ontogeny of nicotinic cholinergic
receptor development
Single dosage given, then sacrifice and brain regions examined for c-fos; GD16, GD18, GD20,
PN0 PN2. C-fos induction maximal on GD20 and PN0, minimal on GD18, no expression on
GD16 and PN2; expression blocked by mecamylamine, a cholinergic antagonist
PND 8-16 critical time – nic exposure resulted in long lasting increase in nicotinic receptors in
cortex, hippocampus and striatum in adults; low affinity binding sites were converted to high
affinity states; no change in mRNA noted
Markers of cell number were reduced (DNA, RNA, protein); elevated ODC – indicating altered
cellular maturation; half of dams failed to give birth
Generalized disruption of receptor acquisition which continued after drug exposure. Cerebellum
primary target of disruption in CNS
pb administration caused hypoxic-ischaemic type effects (reactive hyperinnervation); mp –
selective depression of CNS maturational increases in noradrenaline and dopamine levels and
utilization rates
Effects seen in males only; reduced number of male pups with reduced weight gain postpartum;
alterations in striatal dopaminergic receptor system; postnatal exposure has greater effect than
prenatal exposure
No growth retardation; alterations in nic binding sites, abnormalities in levels of cellular
development markers (ODC, DNA); and impaired development of peripheral noradrenergic
projections
Persistent alterations in the functional state of noradrenergic and dopaminergic neurons, sex
differences noted
Adverse effect upon nic uptake and choline acetyltransferase activity in the cerebral cortex at
time of transition from neurogenesis to synaptogenesis; premature transition from neurogenesis
to synaptogenesis; normal choline acetyltransferase activity in projections to adrenals
Postnatal nic challenge; hyperactivity of ODC to postnatal challenge, also occurred earlier than
controls
Regional specific and maturational specific alteration in adenylate cyclase activity
30 d postpartum; region specific decrease in noradrenaline levels; nic challenge failed to release
noradrenaline
Development of central cholinergic striatum and hippocampal pathways; Regional brain weights
and acetyltransferase activity within normal limits, i.e. no growth retardation. Alterations in the
presynaptic high affinity cholinergic transporter
No brain growth retardation; altered muscarinic M1 receptor development and receptor regulation
mediated by G proteins
3 groups of nic exposure, early gestation, most of gestation, and gestation + 2 wk postpartum;
maternal growth retardation; fetal brain growth retardation significant only in gestation and
postpartum exposure group. ODC unchanged in early group, but elevated in other 2 groups – i.e.
during times of nic receptor development
120
121
122
123
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125
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Drug Safety 2001; 24 (4)
Rat
Nicotine and Smoking Cessation in Pregnancy
© Adis International Limited. All rights reserved.
Nic
Toxin
Animal
Route
Daily dosage
mg/kg/da
3, 6
Nic
Rat
mp
Nic
Rat
mp
Nic
Rat
mp,
pb bid
6
Nic
Rat
mp
2
Nic
Rat
pb
Single dose
Nic
Nic
Rat
Nic
Rat
Nic
ACTH
Rat
Nic
Rat
Nic
Rat
1.5
Outcomeb
Reference
Increased hyperactivity; dopamine concentration increased in substantia nigra, and decreased in
ventral tegmentum area and striatum in those with hyperactivity; the reduction in dopamine was
associated with reduction in number of dopamine D2 receptors
Brain regions examined for marker of cell injury or apoptosis (c-fos); rise in c-fos after GD 8,
initially confined to regions with concentrated nicotinic cholinergic receptors, but later in gestation
more wide spread c-fos expression
Nic GD 4-20; sacrifice PND 7, 15, 22; regional brain contents of neurotransmitters and
metabolites determined; persistent reduction of dopamine turnover in forebrain PND 15 and 22;
persistent reduction in 5HT turnover midbrain, pons-medulla (PND 15), and in forebrain and
cerebellum (PND 22); no effect upon noradrenaline found; route of administration differences
found for transmitter levels and for behavioural tests
PND 1, 7, 14, 28 analysis of brain regions for various nic receptor mRNA; higher α4 and β2 mRNA
levels in hippocampal, septal and cortical regions; maximum effect on PND 14, and generally
resolved by PND 28
Analgesic effect of single dosage (1 mg/kg) of nic in adult rats who had chronic fetal exposure –
shorter analgesic effect, males exhibited shorter effect early in adult hood than females, but by 7
months – no sex differences
Central noradrenergic development – growth stimulatory effect
Decreased brain protein synthesis and degradation; alterations in various amino acid levels.
Increased binding of nic in the brain
Enhanced ability of striatal neurons to synthesize dopamine from tyrosine; increased rate of
dopamine turnover in the striatum of male rats
Pre- and postnatal exposure; effects of postnatal ACTH and nic similar – increased 5HT high
affinity uptake. Prenatal nic exposure – reduced 5HT uptake on PND 21; prenatal ACTH – altered
5HT uptake PND 7
Rat embryos in culture; growth retardation, forebrain and brachial arches (palate formation)
abnormalities
Inhibition of the development of muscarinic receptors in cerebral cortex and cerebellum, and upregulation of nicotinic receptors in cerebral cortex and brainstem
138
139
140
141
142
143
144
145
146
147
148
149
150
151
152
153
154
Dempsey & Benowitz
Drug Safety 2001; 24 (4)
Peripheral nervous system, cardiovascular, respiratory or response to stress studies (studies related to SIDS)
Smk
Mice
IH
Electron microscopic alterations of sciatic nerves
Nic
Rat
pb
10
Single dosage, bolus, subcutaneous. Functional nicotinic receptors are present in adrenal
medulla prior to functional splanchnic innervation
Nic
Rat
pb
Neonatal rat adrenals secrete catecholamines by a mechanism that does not include nerve
stimulation. Hypoxia and nic both appear to simulate secretion by exocytosis.
Nic
Rat
pb
0.05
Accelerated maturation of motor end-plate (postnatal administration)
Nic
Rat
pb
0.5
Accelerated maturation of developing nerve and muscle. Altered contractile force, speed,
isometric twitch, and tetanus half-contraction duration. Increased cellular metabolic activity and
hypertrophy of adrenal glands
Nic
Rat
pb
2
No difference in dosage dependent response to noradrenaline. Shift to right in chronotropic effect
of cumulative dosage response curves; and reduced binding (without change in affinity) of 3Hdihydroalprenolol
308
© Adis International Limited. All rights reserved.
Appendix III. Contd
mp
6
Nic
Rat
mp
6
Nic
Nic
Nic
Rat
Rat
Rat
mp
5
mp
2, 6
Nic
Rat
mp
6
Nic
Rat
mp
12
Nic
Rat
mp
Neuroendocrine
Smk
Rat
Nic
Rat
Nic
Rat
IH
po
pb
2.4, 4.5
0.1, 6
Nic
Rat
pb
0.1, 6
Nic
Nic
Rat
Rat
pb
mp
0.1, 6
2, 6
Nic
Rat
mp
Morphology
Smk
Rat
IH
10 min tid
Smk
Rat
IH
1 mg/m3 air
Smk
Rat
IH
Smk
mouse
IH
Max tolerated
dosage
10 min tid
Smkless tob
mouse
po-g
3.2, 6.4
Kidney and heart tissue preparation: increased basal levels of membrane adenylate cyclase,
supersensitivity to isoproterenol – altered responsiveness without changes in receptor binding
Delayed development of cardiac β-adrenergic receptor binding capabilities and subsensitivity of
chronotropic responses to isoproterenol
Transient/reversible alteration in cutaneous axon reflexes
Decreased sensitivity of peripheral arterial chemoreceptors to hyperoxic test on PN-3
Hypoxic challenge (60 or 75 min) 5% O2. Mortality increased in 6mg group but not in 2mg or
control pups. Neurotransmitter levels studied in 6mg and control pups only. No difference: basal
adrenal catecholamine levels, basal CNS noradrenaline levels. Significant differences: decreased
adrenal catechlolamine release in response to hypoxic challenge, decreased cardiac β receptor
binding capabilities, decreased CNS noradrenaline turnover, but increased CNS noradrenaline
release in response to hypoxia
Postpartum response to 10 min hypoxia and hypercarbia (10% O2, 15% O2; 5% CO2). Response
unaffected by prenatal nic exposure
Maternal plasma nicotine concentration 134 ± 42 µg/L. Fetal growth retardation. No difference in
response to anoxia
PND 1-2, exposed and controls – similar HR, ECG, and RR in 21% O2. 10 minutes of 5% O2 –
normal response is tachycardia; exposed pups had rapid decline in heart rate
Delay of LH surge during proestrous (dosage-dependent); prolactin unaffected
Disrupted normal pattern of LH release in offspring
Stress – restraint, PND 120. male rats who were prenatally exposed to nic; baseline ACTH,
prolactin, corticosterone all similar; no difference in corticosterone response; ACTH elevated in
6mg dosage group; prolactin significantly reduced in 6mg dosage group
Single nic challenge dosage in PND 120; males – ACTH response blunted in high dosage group
only; prolactin response blunted in high dosage group and enhance in low dosage group
Complex pharmacological challenges; no augmentation of prolactin or ACTH s/p challenges
Males had CNS aromatase activity similar to females on PND 6, critical time for brain sex
differentiation
Testosterone rise abolished on GD 18 in males; altered normal sex difference preferences for
saccharine
Effect more pronounced with high yield smk exposure: changes in neural plate, neural tube,
surface ectoderm, pericardium, and heart
No maternal growth retardation, small but significant fetal growth retardation; no difference in
ossification, litter size; no malformations
No skeletal malformations
Exposure during selected gestational periods; dosage-related embryo growth retardation;
exposure on GD 0-1 resulted in growth retardation, with a lag prior to catch up growth; delayed
ossification; no malformations among genetically normal mice; small increase in malformation
among mice with high baseline rate of malformations
Maximum nic plasma concentrations were 44 and 79 µg/L. Fetal weight reduction, delayed
ossification, increased haemorrhages and lethality
155
156
157
158
159
160
161
162
163
164
165
166
167
168
169
170
171
172
137
174
Continued on next page
309
Drug Safety 2001; 24 (4)
Rat
Nicotine and Smoking Cessation in Pregnancy
© Adis International Limited. All rights reserved.
Nic
Toxin
Animal
Route
Smkless tob
mouse
po-g
Daily dosage
mg/kg/da
4, 12, 20
Smkless tob
mouse
po-g
12, 20, 36, 60
Smkless tob
Rat
po-g
4, 18
Nic
Nic
Nic
mouse
Rat
Rat
po-g
pb
mp
36
16.7
3.5
Nic
Rat
mp
75, 150 µg/h
Palate, jaw and teeth formation studies
Nic
Mouse
pb
1.67
Nic
Mouse
pb
1.67
Nic
Nic
Mouse
Mouse
pb
1.67
1.67
Nic
Nic
Mouse
Mouse
pb
pb
1.67
1.67
Nic
Rat
Miscellaneous and in vitro studies
Smk
mice
IH
Smk
hamster
IH
Smk
hamster
in vitro
Outcomeb
Reference
Mean plasma nic concentrations were 99, 398, and 623 µg/L; low dosage produced negligible
effects on dams and fetuses – precocious ossification in 60% of low dosage fetuses
Mean nic plasma 368 and 481 µg/L; decreased ossification; no increased malformations; fetal
growth retardation and increased resorption
Plasma nic 283 µg/L (4mg dosage), 846 µg/L (18 mg/dosage); maternal weight gain reduced,
fetal bodyweight gain reduced at high dosage only; no difference in malformations; dosage
dependent reduction in ossification
Reduced ossification in 5/19 measurements of bone ossification
Significant effect upon morphological development
No abnormalities seen in control, nic only or caffeine only groups; but delayed ossification seen in
combined nic and caffeine group
Embryonic development retardation, no dysmorphogenesis
175
Nic-exposed animals (n = 130): 9.6% cleft palates, fetal growth retardation. Controls (n = 348):
0% cleft palates
Fetal growth retardation, odontogenesis retarded (dentin and enamel formation) among those
with cleft palates
Retarded molar development among those with cleft palates
9.6% of nic exposed had cleft palates (n = 130) (controls n = 348); abnormal molar development,
type of abnormality dependent upon presence or absence of cleft palate
Among those with cleft palate (9.6%), there was retardation of developing incisors.
Very abnormal tongue development among those with cleft palates; those without cleft palates
were similar to controls with some minor abnormalities
Rat embryos in culture; growth retardation, forebrain and brachial arches (palate formation)
abnormalities
310
© Adis International Limited. All rights reserved.
Appendix III. Contd
176
177
178
179
180
181
182
183
184
185
186
187
147
Dempsey & Benowitz
Drug Safety 2001; 24 (4)
Increased number of micronucleated polychromatic erythrocytes in fetal liver
188
Daily smoking for 30d prior to mating; abnormalities found in most ovarian and uterine parameters 189
Oviduct explants in chambers with smk dose-dependent inhibition of transport of oocyte
190
complex, gas phase more inhibitory than particulate phase
Nic
Rat
in vitro
Inhibited iron transport but it required dosages so high that this cannot be postulated as a mechanism in
191
humans
Nic
mouse
in vitro
Very high dosages adversely affected embryonic development
192
Smk
in vitro
Inhibition of ciliary beat frequency; side stream fraction without oxidant gases did not inhibit ciliary 193
beat
a Dosage is in mg/kg/day unless other wise specified. Inhaled dosages are in time.
b All studies include unexposed control groups. The outcome is in comparison to the control, unless otherwise specified.
ACTH = adrenocorticotrophic hormone; bid = twice daily; c-fos = cellular marker (indirect measure of cell death); CNS = central nervous system; d = day; ECG = electrocardiogram;
EtOH = ethanol; GD = gestational day; IH = inhalation; LH = leutenising hormone; mp = implanted osmotic minipump; Nic = nicotine; ODC = ornithine decarboxylase (sensitive
measure of cell injury); PaO2 = arterial oxygen tension; patch =transdermal nicotine patch; pb = parental route (peritoneal or subcutaneous), bolus administration; PND = postnatal
day; PNS = peripheral nervous system; po = oral (drinking water); po-g = oral-gavage; RR = respiratory rate; SIDS = sudden infant death syndrome; Smk = tobacco smoke; Smkless
tob = smokeless tobacco extract; s/p = status post; tid = 3 times daily; 5HT = serotonin (5-hydroxytriptamine).
bid
Toxic agent
Target
Effect of toxic agent
Reference
Effects on the placenta
Maternal smoking
Placenta
No difference in weight
203
Maternal smoking
Placenta
No difference in weight
204
Maternal smoking
Placenta
No difference in weight
205
Maternal smoking
Placenta
No difference in weight
206
Maternal smoking
Placenta, all trimesters
Smaller placentas
207
Maternal smoking
Placental volume, GA18 sonogram
Larger placentas with >15 cigarettes/d
208
Maternal smoking
Placenta
No difference in weight
209
Morphological effects
Maternal smoking
Placenta
Increased subchorionic fibrin deposits, calcifications; thinner, rounder placentas
204
Maternal smoking
Placenta
Atrophic and hypovascular changes in villi
Maternal smoking
Placenta
No difference in spiral arteries
210
Maternal smoking
Placenta, term
Reduced capillary volume fraction; increased thickness of villous membrane
211
Maternal smoking
Placenta, term
Langhans cells, decreased number
212
Maternal smoking
Umbilical cord
Heavy smoking associated with abnormal vascular cross-sectional profiles
213
Maternal smoking
Placenta, all trimesters
Abnormalities of microvilli, focal syncytial necrosis, decreased syncytial pinocytotic activity,
increased mean thickness of basement membranes (trophoblastic layer and fetal capillary),
increased collagen in villous stroma, shrinkage endothelial changes in fetal capillaries
207
Maternal smoking
Placenta, early first trimester
Reduction in chorionic villi cell columns, important for attachment of placenta to uterus
214
Maternal smoking
Placenta
Increased surface and villous calcifications; villous calcifications decreased with concomitant
maternal intake of tocopherol (vitamin E), betacarotene and ascorbic acid (vitamin C)
215
Nicotine and Smoking Cessation in Pregnancy
© Adis International Limited. All rights reserved.
Appendix IV. Mechanisms of toxicity: maternal, placental, and fetal studies in humans
Cellular effects
Maternal smoking
Maternal plasma
Lower pregnancy-specific β-1-glycoprotein
216
Maternal smoking
Amniotic fluid
Elevated noradrenaline, vanillyl mandelic acid, and dopamine metabolite levels
217
Maternal smoking
Placenta, term normal
Collagen production approximately doubled
218
Maternal smoking
Placenta, amnion
Placenta – increased fibronectin production; amnion – decreased fibronectin production
219
None
Placenta
HME expressed in normal placental tissue (HME expressed in alveolar macrophages of adult
smokers, HME may be affected by smoking during pregnancy)
220
Reduced production of L-citruline, and, L-arginine (important for nitric oxide synthesis)
221
Maternal smoking
Decreased nitric oxide synthetase activity
222
Effects on amino acid transport
Nicotine
Placental vesicles;
Nicotine and ethanol
perfused placental cotyledon
No decreased transport of probe amino acid
223
Maternal smoking
Block of acetylcholine amino acid transport
224
Placental chorionic villi
Placenta
Continued on next page
311
Drug Safety 2001; 24 (4)
Effects on nitric oxide synthesis
Maternal smoking
Umbilical artery segments
312
© Adis International Limited. All rights reserved.
Appendix IV. Contd
Toxic agent
Target
Effect of toxic agent
Reference
Nicotine
Placental syncytiotrophoblast
vesicles
Glycine transport inhibited in fetal facing basal plasma membrane, but not maternal facing
membrane
225
Effects on growth factors
Maternal smoking
Placental
Impaired EGF receptor bioactivity, especially in SGA babies
226
Benzo(a)pyrene
Placental cell culture
Inhibits EGF binding and autophosporylation
227
Benzo(a)pyrene
Human placental trophoblastic
chorionic cell culture
Decreased EGF binding; decreased concentration of EGF protein receptors; decreased
trophoblast proliferation; reduced hCG secretion
228
Maternal smoking
Maternal serum
Lower VEGF (VEGF positively correlate with GA, serum hCG and serum progesterone)
229
Maternal smoking
Maternal plasma
Lower hPL
230
Maternal smoking
Maternal serum
Elevated hPL, no significant difference in BW
231
Maternal smoking
Maternal serum, newborn serum
Lower maternal prolactin and estradiol levels; lower neonatal estradiol levels; unaffected
neonatal prolactin levels
232
Nicotine, cotinine
Granulosa luteal cells from in vitro
fertilisation patients
Cultured cells synthesised progesterone; synthesis unaffected by nicotine or cotinine
233
Nicotine, cotinine
Fetal adrenal tissue
Nicotine and continine competitively inhibited 11 β-hydroxylase; nicotine but not cotinine
competitively inhibited 12-hydroxylase activity
234
Maternal smoking
Maternal serum
If female fetus – altered hPL, hCG; if male fetus – altered estradiol, prolactin; higher hCG if
fetus female than if male
235
Cigarette smoke extract,
alkaloids
Granulosa cell cultures
MA-10 cell cultures
Cell growth and progesterone synthesis inhibition by CS extract, nicotine, cotinine, or anabasine 236
Nicotine
Nicotine and ethanol
Tissue culture, human placenta, rat
placenta
No effect on 11 β-hydroxysteroid dehydrogenase; (controls fetal and placental glucocorticoid
exposure)
237
Lower serum hPL, lower urinary estriol, lower conversion of dehydroepiandrosterone sulfate to
estradiol
238
Endocrine effects
Effects on estrogen synthesis
Maternal smoking
Maternal serum and urine
Placental tissue
Aromatase activity unaffected
239
Nicotine alkaloids
Choriocarcinoma cell culture
All inhibited androstenedione conversion to estrogen
240
Maternal smoking
Maternal serum
Estrogen levels 10% lower
241
Maternal smoking
Placenta tissue
Lower aromatase, higher aryl hydroxylase activity
242
Cigarette smoke extract,
tobacco leaf extract
Enzyme kinetic studies
Aromatase inhibition; N-(N-octanoyl)nornicotine has highest inhibition
243
Acyl analogues of nicotine
and anabasine
Placental microsomes
breast tumour cells
N-(N-octanoyl)nornicotine, N-(4-hydroxy-undecanoyl) anabasine
potent inhibitors of estrogen synthesis
244
Effects on prostaglandins and related compounds
Nicotine
Umbilical artery segments
Decline in prostacyclin production
245
Maternal smoking
Umbilical artery segments
Reduced prostacyclin production
246
Maternal smoking
Umbilical artery and vein segments
Reduced PGE2 synthesis in veins
247
Dempsey & Benowitz
Drug Safety 2001; 24 (4)
Maternal smoking
Cultured endothelial cells from
umbilical arteries
Reduced endothelial cell growth in culture; reduced prostacyclin production
248
Maternal smoking
Maternal serum, newborn serum
Newborn prostacyclin-simulating activity reduced; maternal activity reduced but not significantly 249
Nicotine, very high
concentrations
Umbilical artery specimens,
umbilical cord platelet
Prostacyclin and thromboxane A2 production in arteries unaffected by nicotine; platelet
250
production of thromboxane A2 reduced by 7%; super-physiological concentration of nicotine, 10
to 10 000 mg/L used (physiological nicotine levels <100 µg/L)
Maternal smoking
Umbilical cord blood
No effect upon prostaglandin-dependent platelet aggregation (n = 20)
251
Maternal smoking
Umbilical artery segments
Decreased prostacyclin like activity; no correlation with cotinine levels, (n = 38)
252
Maternal smoking
Umbilical artery segments
Decreased prostacyclin like activity (n = 84); weak correlation with cotinine levels
253
Maternal smoking
Maternal urine, newborn urine
No difference in prostacyclin and thromboxane A2 metabolite levels
254
Maternal smoking
Newborn urine
No difference in prostacyclin metabolite levels
255
Maternal smoking
Amniotic fluid
Elevated prostaglandin E2 and F2α levels
217
Maternal smoking
Umbilical artery segments
Reduced prostacyclin production
221
Nicotine, cotinine
Placental tissue
Activates placental phospholipase-A2-like enzymes
21
Cigarette smoke extract,
nicotine, cotinine
Decidual macrophages, maternal
blood macrophages, maternal blood
monocytes
CS extract inhibited, nicotine and cotinine did not inhibit secretion of platelet activating factoracetylhydrolase
256
Effects on immunological function
Maternal smoking
Maternal serum
50% increase in secretory component of immunoglobulin A
257
Effects on haematological parameters
Maternal smoking
Umbilical cord blood
All higher: haemoglobin, haematocrit, red cell count, mean corpuscular haemoglobin
258
Higher haematocrit levels; haematocrit correlated with maternal smoking; haematocrit
correlated with maternal thiocyanate level; inverse correlation between haematocrit and
ferritin
259
Maternal smoking
Newborn blood
Maternal blood
Elevated haematocrits (41 to 47%) associated with decreased birth weight
260
Maternal smoking
Newborn blood
Haemoglobin increased and O2 tension for 50% of HbO2 saturation (P50) decreased with
increased maternal smoking; P50 decrease due to increased Hb-F
261
Maternal smoking
Maternal platelets
Platelet aggregation – increased reactivity
262
None
Maternal blood
placenta
High maternal haemoglobin (>130 mg/L) associated with low BW, acute infarcts, and syncytial
knots of the placenta
263
None
Maternal blood
Negative correlation between haemoglobin level and levels of hCG and hPL
264
Maternal smoking
Maternal serum
Increased ceruloplasmin, without a difference in serum ferroxidase activity, indicating loss of
ceruloplasmin ferroxidase activity
265
Maternal smoking
Umbilical cord blood
Elevated erythropoietin, elevated haematocrit
266
Maternal smoking
Maternal blood, birth weight
Among smokers, third trimester haemoglobin levels inversely associated with birth weight
267
Maternal smoking
Umbilical cord blood
Elevated erythropoeitin, positive correlation with number of cigarettes/d
(erythropoeitin marker for chronic hypoxia)
268
BW = birthweight; CS = cigarette smoke; EGF = epidermal growth factor; GA = gestational age; Hb-F = fetal haemoglobin; HbO2 = haemoglobin oxygen; hCG = human chorionic
gonadotrophin; HME = human macrophage metalloelastase; hPL = human placental lactogen; PGE2 = prostaglandin E2; SGA = small for gestational age; VEGF = vascular endothelial
growth factor.
313
Drug Safety 2001; 24 (4)
Maternal smoking
Nicotine and Smoking Cessation in Pregnancy
© Adis International Limited. All rights reserved.
Maternal smoking
314
Dempsy & Benowitz
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Correspondence and offprints: Dr Neal L. Benowitz, University of California, San Francisco Box 1220 San Francisco, CA
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E-mail: [email protected]
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